OXAZOLIDIN-2-ONA COMPOUNDS AS PI3KS INHIBITORS, THEIR USES, AND PHARMACEUTICAL COMPOSITION

专利摘要:
oxazolidin-2-one compounds as pi3ks inhibitors, their uses, and pharmaceutical composition. the present invention relates to pyrimidine-substituted oxazolidin-2-dione compounds that act as pi3k inhibitors (phosphatidylinositol-3-kinase), as well as pharmaceutical compositions thereof, methods for their manufacture and uses for the treatment of conditions, diseases and pi3k dependent disorders.
公开号:BR112014020672B1
申请号:R112014020672-4
申请日:2013-02-22
公开日:2020-09-01
发明作者:Giorgio Caravatti；Robin Alec Fairhurst；Pascal Furet；Frédéric Stauffer；Frank Hans Seiler；Heinrich Rueeger；Clive McCarthy
申请人:Novartis Ag；
IPC主号:

专利说明:

FIELD OF THE INVENTION
[001] The present invention relates to pyrimidine-substituted oxazolidin-2-dione compounds that act as PI3K inhibitors (phosphatidylinositol-3-kinase), as well as pharmaceutical compositions thereof, methods for their manufacture and uses for treatment of PI3K-dependent conditions, diseases and disorders. BACKGROUND OF THE INVENTION
[002] Phosphatidylinositol-3-kinases (PI3Ks comprise a family of lipid kinases that catalyze the transfer of phosphate from the D-3'position of inositol lipids to produce phosphoinositol-3-phosphate (PIP), phosphoinositol-3,4-diphosphate ( PIP2) and phosphoinositol-3,4,5-triphosphate (PIP3) which, in turn, act as secondary messengers in signaling cascades by anchoring proteins that contain homology to pleckstrin, FYVE, Phox and other phospholipid-binding domains in a variety of frequent signaling complexes on the plasma membrane (Vanhaesebroeck et al., Annu. Rev. Biochem 70: 535 (2001); Katso et al., Annu. Rev. Cell Dev. Biol.17: 615 (2001)) Of the two Class 1 PI3Ks, Class 1A PI3Ks are heterodimers composed of a p110 catalytic subunit (α, β, δ isoforms) constitutively associated with a regulatory subunit that can be p85α, p55α, p50α, p85β or p55y. Class 1B has a family member, a heterodimer composed of a subunit catalytic activity p110y associated with one of the two regulatory subunits p101 or p84 (Fruman et al., Annu Rev. Biochem. 67: 481 (1998); Suire et al., Curr. Biol. 15: 566 (2005)). The modular domains of the p85 / 55/50 subunits include the Homology to Src (SH2) domains that bind phosphotyrosine residues in a specific sequence context on the activated receptor and cytoplasmic tyrosine kinases, resulting in the activation and localization of Class 1A PI3Ks. Class 1B PI3K is activated directly by G protein-coupled receptors that bind a diverse repertoire of peptide and non-peptide ligands (Stephens et al., Cell89: 105 (1997)); Katso et al., An- nu. Rev. Cell Dev. Biol.17: 615-675 (2001)). Consequently, the phospholipid products resulting from PI3K Class 1 bind upstream receptors with downstream cellular activities including proliferation, survival, chemotaxis, cell traffic, motility, metabolism, inflammatory and allergic responses, transcription and translation (Cantley et al., Cell64: 281 (1991); Escobedo and Williams, Nature335: 85 (1988); Fantl et al., Cell69: 413 (1992)). In several cases, PIP2 and PIP3 recruit Akt, the human homologous product of the viral oncogene v-Akt, to the plasma membrane where it acts as a nodal point for several intracellular signaling pathways important for growth and survival (Fantl et al. , Cell69: 413-423 (1992); Bader et al., Nature Rev. Cancer 5: 921 (2005); Vivanco and Sawyer, Nature Rev. Cancer 2: 489 (2002)). The aberrant regulation of PI3K, which often increases survival through Akt activation, is one of the most prevalent events in human cancer and has been shown to occur at multiple levels. The tumor suppressor gene PTEN, which dephosphorylates phosphoinositides at the 3 'position of the inositol ring and in doing so antagonizes PI3K activity, is functionally deleted in a variety of tumors. In other tumors, the genes for the p110α isoform, PIK3CA, and for Akt are amplified and the increased protein expression of their products has been demonstrated in several human cancers. In addition, the p85a mutations and translocation that serve to upregulate the p85-p110 complex, have been described in human cancers. Finally, somatic "missense" mutations in PIK3CA that activate downstream signaling pathways, have been described at significant frequencies in a wide range of human cancers (Kang at el., Proc. Natl. Acad. Sci. USA 102: 802 ( 2005); Samuels et al., Science 304: 554 (2004); Samuels et al., Cancer Cell 7: 561- 573 (2005)).
[003] In some tumors, the isoform of p110β, PIK3CB is amplified and overexpressed. In addition, studies indicate that tumors driven by loss of PTEN may be sensitive to p110β instead of p110a. (Jia et al., Nature, 454: 776-779 (2008). Wee et al., PNAS 105 (35), 13057-13062 (2008); Liu et al., Nature Rev. Drug Discovery 8: 627-644 (2009)).
[004] Both p110δ and p110y are expressed primarily in the hematopoietic system and appear to play significant roles in leukocyte signaling (Liu et al. Blood110 (4), 1191-1198 (2007)). However, they also play roles in some cancers (Knobbe et al., Brain Pathol.13, 507-518 (2003); Kang et al. PNAS 103 (5), 1289-1294 (2006)). The expression of p110δ is restricted to leukocytes, pointing to its potential role in leukocyte-mediated diseases (Vanhaesebroeck et al. PNAS 94 (9), 4330-4335 (1997)). p110δ is up-regulated in blast cells in patients with acute myeloid leukemia, where it plays an important role in cell survival (Sujobert et al., Blood106 (3), 1063-1066 (2005)) indicating its potential as a target in leukemia and other haematological malignancies. Activation of p110δ plays an important role in the development of B cell malignancies and therefore inhibition of p110δ can be used to treat B cell malignancies such as chronic lymphocytic leukemia (LLC), non-Hodgkin's lymphoma (NHL) ), plasma cell myeloma and Hodgkin's (NH) lymphoma Castillo et al., Expert Opin. Investig. Drugs21, 15-22 (2012)).
[005] These observations show that deregulation of phospho-nositol-3 kinase and the upstream and downstream components of this signaling pathway is one of the most common deregulations associated with human cancers and proliferative diseases (Parsons et al., Nature436: 792 (2005); Hennessey at el., Nature Rev. Drug Disc. 4: 988-1004 (2005)).
[006] Published international patent application W02007 / 084786 describes substituted pyrimidine molecules that inhibit PI3K. SUMMARY OF THE INVENTION
[007] There remains a need for compounds that inhibit the activity of more than one of the PI3K Class I isoforms (alpha, beta, delta and gamma), because such compounds are considered to have the ability to prevent adaptation mechanisms due to rewiring through other isoforms, compared to compounds with unique specificity, for example, specificity by a member of the PI3K Class I family.
[008] The increased inhibition potency of at least one of the PI3K isoforms (i.e., in inhibition of at least one PI3K isoform in lower concentrations, especially one or both of the alpha and beta isoforms) can also be advantageous. In the case of null tumors for PTEN, for example, although the targeting isoform is p110b, complete efficacy may require the participation of other Class IA isoforms. There is also a need for compounds that potentially inhibit PI3K alpha kinase, for example, for the treatment of cancers that are primarily driven by the oncogenic forms of the gene encoding p110a (for example, PIK3CA H1047R or E545K), as well as tumors that show a increased number of copies of PIK3CA.
[009] Compounds that show selective inhibition in favor of one or more isoforms of PI3K (for example, at least two, preferably three of the alpha, beta, delta and gamma isoforms, for example, the alpha, beta and delta isoforms) compared with mTOR are also desirable, since the inhibitory effect of mTOR generally reduces the safety window, more especially when the compounds inhibit mTOR more markedly than PI3K (unfavorable proportion).
[0010] In addition, PI3K inhibitors that have a reduced effect, in particular, that do not have an off-target effect, such as tubulin binding, are desired, since such an effect can cause toxic effects not connected with inhibition of PI3K in the target and, therefore, such compounds may require careful dosage control to ensure that the therapeutic effect is controllable and attributable to the inhibition of PI3K. Therefore, there is a need for compounds that have a reduced or weak off-target effect or that have no off-target effect.
[0011] Desirable compounds that show an improved inhibition of at least one (for example, PISKalfa), but especially two (for example, PI3Kalfa and PI3Kbeta) or three (for example, PI3Kalfa, PI3Kbeta and PI3Kdelta) or all four PI3Ks of Class 1 (for example, PI3Kalfa, PI3Kbeta, PI3Kdelta and PI3Kgama) as well as a reduced off-target effect (in particular, in the absence of) are sought.
[0012] The present invention provides compounds and pharmaceutical compositions thereof, the compounds of which are PI3K inhibitors. The invention also provides combinations that comprise these compounds. The invention further provides the compounds of the invention for use in the methods of treating, preventing or ameliorating a PI3K-mediated disease such as cancer, which comprises administering to an individual in need an effective amount of a compound that inhibits PI3K of the invention. The invention also provides intermediates useful in the preparation of the compounds of the invention.
[0013] The present invention provides, in one aspect, a compound of Formula (I)
on what,

[0014] R1 = where R1a = H or -CH3

[0015] or R1 = where D = deuterium;
[0016] R2 = H and R3 = H;
[0017] R4 = H, and R5 = -CH3 or -CH2OH; or
[0018] R4 = -CH2OH, and R5 = H;
[0019] or
[0020] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[0021] R3 = H;
[0022] R4 = -CH3, -CH2OH, -CH2CH2OH, -CH2CH (OH) CH3OU CH2C (OH) (CH3) 2 and R5 = H, OR
[0023] R4 = H, and R5 = -CH3, -CH2OH, -CH2CH (OH) CH3 or - CH2C (OH) (CH3) 2, OR
[0024] R4 = H or -CH3 and R5 = H or -CH
[0025] or
[0026] R3 = H and R4 = H;
[0027] R2 and R5 are linked and form the group - (CH2) 4-;
[0028] or
[0029] R4 = H and R5 = H; and
[0030] R2 = -CH2OH, and R3 = -CH3; or
[0031] R2 = H or -CH3, and R3 = -CH2OH;
[0032] or
[0033] R2 = H and R4 = H; and
[0034] R3 and R5 are linked and form 0 group
or 0 group
or
[0035] R3 = H and R5 = H; and
[0036] R2 and R4 are linked and form the group
or a pharmaceutically acceptable salt thereof.
[0037] The wavy line indicates the coupling point of the morpholine and also when present, the coupling point of other groups shown, to the rest of the molecule. Throughout the description, the sign "=" has the standardized meaning of "equal" and in the definitions of the invention can be replaced by "equal" or "is" or "represents". For example, the phrase "R3 = H" can be read as "R3 is H" or "R3 represents H".
[0038] The compounds of Formula (I) are considered suitable, for example, for use in the treatment of PI3 kinase dependent diseases, especially proliferative diseases such as cancer, for example, tumor diseases.
[0039] The invention can be more fully appreciated with reference to the following description, which includes the definitions mentioned and the conclusive examples. The described modalities can be taken independently, collectively or in any combination unless otherwise stated. As used here, the terms "including", "containing" and "comprising" are used in their open, non-limiting sense.
[0040] Unless otherwise specified, the term "compounds of the present invention" or "a compound of the present invention" and the like refers to compounds of Formula (I) and their subFormulas (for example, Formulas (IA ) and (IA ')) and salts of the compounds, as well as isotopically labeled compounds (including substitutions with deuterium).
[0041] The compounds of the invention have the stereochemistry illustrated in Formula (I) and its subFormulas, unless otherwise stated. BRIEF DESCRIPTION OF THE FIGURES
[0042] Figure 1 is a graph of the exploratory differential calorimetry of the crystalline material of Example 10.
[0043] Figure 2 is the X-ray powder diffraction plot of the crystalline material of Example 10.
[0044] Figure 3 is a graph of the differential scanning calorimetry of the crystalline material of Example 18, lot A.
[0045] Figure 4 is the X-ray powder diffraction plot of the crystalline material of Example 18, lot B.
[0046] Figure 5 is a graph of the differential scanning calorimetry of the crystalline material of Example 18, lot B.
[0047] Figure 6 is the X-ray powder diffraction plot of the crystalline material of Example 18, lot B.
[0048] Figure 7 is a graph of the differential scanning calorimetry of the crystalline material of Example 18, lot C.
[0049] Figure 8 is the X-ray powder diffraction plot of the crystalline material of Example 18, lot C.
[0050] Figure 9 is a graph of the differential scanning calorimetry of the crystalline material of Example 18, lot D.
[0051] Figure 10 is the X-ray powder diffraction plot of the crystalline material of Example 18, lot D.
[0052] Figure 11 is a graph of the differential scanning calorimetry of the crystalline material of Example 18, lot E.
[0053] Figure 12 is the X-ray powder diffraction plot of the crystalline material of Example 18, lot E. DETAILED DESCRIPTION
[0054] Various embodiments of the invention are described herein. It will be recognized that the features specified in each embodiment can be combined with other features specified to provide additional embodiments of the present invention. Various (enumerated) embodiments of the invention are also described herein.
[0055] The present invention provides in one aspect a compound according to Formula (I):
on what,
on what
[0056] R1a = H or -CH3

[0057] or R1 = where
[0058] D = deuterium;
[0059] R2 = H and R3 = H;
[0060] R4 = H, and R5 = -CH3 or -CH2OH; or
[0061] R4 = -CH2OH, and R5 = H;
[0062] or
[0063] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[0064] R3 = H;
[0065] R4 = -CH3, -CH2OH, -CH2CH2OH, -CH2CH (OH) CH3OU - CH2C (OH) (CH3) 2 and R5 = H, OR
[0066] R4 = H, and R5 = -CH3, -CH2OH, -CH2CH (OH) CH3 or - CH2C (OH) (CH3) 2, OR
[0067] R4 = H or -CH3 and R5 = H or -CH3
[0068] or
[0069] R3 = H and R4 = H;
[0070] R2 and R5 are linked and form the group - (CH2) 4-;
[0071] or
[0072] R4 = H and R5 = H; and
[0073] R2 = -CH2OH, and R3 = -CH3; or
[0074] R2 = H or -CH3, and R3 = -CH2OH;
[0075] or
[0076] R2 = H and R4 = H; and
[0077] R3 and R5 are linked and form 0 group
or 0 group
or
[0078] R3 = H and R5 = H; and
[0079] R2 and R4 are linked and form 0 group
or a pharmaceutically acceptable salt thereof.
[0080] In a preferred embodiment of this aspect, a compound according to θ Formula (I) is provided in which,

[0081] R1 = where
[0082] R1a = H or –CH3
[0083] or R1 =

[0084] where
[0085] D = deuterium;
[0086] R2 = H and R3 = H;
[0087] R4 = H, and R5 = -CH3 or -CH2OH; or
[0088] R4 = -CH2OH, and R5 = H;
[0089] or
[0090] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[0091] R3 = H;
[0092] R4 = -CH3, -CH2OH, -CH2CH2OH, -CH2CH (OH) CH3OU - CH2C (OH) (CH3) 2 and R5 = H, or
[0093] R4 = H, and R5 = -CH3, -CH2OH or
[0094] R4 = H or -CH3 and R5 = H OR -CH3
[0095] or
[0096] R3 = H and R4 = H;
[0097] R2 and R5 are linked and form the group - (CH2) 4-;
[0098] or
[0099] R4 = H and R5 = H; and
[00100] R2 = -CH2OH, and R3 = -CH3; OR
[00101] R2 = H or -CH3, and R3 = -CH2OH;
[00102] or
[00103] R2 = H and R4 = H; and
[00104] R3 and R5 are linked and form 0 group
or 0 group
or
[00105] R3 = HeR5 = H; and
[00106] R2 and R4 are linked and form 0 group
or a pharmaceutically acceptable salt thereof.
[00107] In a more preferred embodiment of this aspect, a compound according to Formula (I) is provided in which

[00108] R1 = where
[00109] R1a = H or -CH3

[00110] or R1 = where
[00111] D = deuterium;
[00112] R2 = H and R3 = H;
[00113] R4 = H, and R5 = -CH3 or-CH2OH; or
[00114] R4 = -CH2OH, and R5 = H;
[00115] or
[00116] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[00117] R3 = H;
[00118] R4 = -CH3, -CH2OH, -CH2CH2OH, -CH2CH (OH) CH3OU - CH2C (OH) (CH3) 2 and R5 = H, or
[00119] R4 = H, and R5 = -CH3 or -CH2OH, or
[00120] R4 = H or -CH3 and R5 = H or -CH3;
[00121] or
[00122] R3 = H and R4 = H;
[00123] R2 and R5 are linked and form - (CH2) 4-;
[00124] or
[00125] R4 = H and R5 = H; and
[00126] R2 = -CH2OH, and R3 = -CH3; or
[00127] R2 = H or -CH3, and R3 = -CH2OH; or or a pharmaceutically acceptable salt thereof.
[00128] In a further preferred embodiment, a compound of Formula (I) is provided
on what,

[00129] where
[00130] R1 = R1a = H or -CH3

[00131] or R1 = where
[00132] D = deuterium;
[00133] R2 = H and R3 = H;
[00134] R4 = H, and R5 = -CH3 or -CH2OH; or
[00135] R4 = -CH2OH, and R5 = H;
[00136] or
[00137] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[00138] R3 = H;
[00139] R4 = -CH3, -CH2OH or -CH2CH2OH and R5 = H, or
[00140] R4 = H, and R5 = -CH3 or -CH2OH, or
[00141] R4 = H or -CH3 and R5 = H OR -CH3
[00142] or
[00143] R3 = H θ R4 = H;
[00144] R2 and R5 are linked and form the group - (CH2) 4-;
[00145] or
[00146] R4 = H and R5 = H; and
[00147] R2 = -CH2OH, and R3 = -CH3; or
[00148] R2 = H or -CH3, and R3 = -CH2OH; or a pharmaceutically acceptable salt thereof.
[00149] In an additional preferred alternative embodiment, a compound according to Formula (I) is provided
on what,

[00150] R1 = where
[00151] R1a = H or –CH3

[00152] ouR1 = where
[00153] D = deuterium;
[00154] R2eR3 = H;
[00155] R4 = H, and R5 = -CH3 or -CH2OH; or
[00156] R4 = -CH2OH, and R5 = H;
[00157] or
[00158] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[00159] R3 = H;
[00160] R4 = -CH3, -CH2OH and R5 = H, or
[00161] R4 = H, and R5 = -CH3, -CH2OH, or
[00162] R4 = R5 = H or-CH3
[00163] or
[00164] R3 = H and R4 = H;
[00165] R2 and R5 are linked and form - (CH2) 4-;
[00166] or
[00167] R4 = HeR5 = H; and
[00168] R2 = -CH2OH, and R3 = -CH3; or
[00169] R2 = H or -CH3, and R3 = -CH2OH; or a pharmaceutically acceptable salt thereof.
[00170] Regarding Formula (I) in any of the above mentioned modalities, the following detailed description is provided. R1a
[00171] In one embodiment, R1a is H.
[00172] In another embodiment, R1a is -CH3.
[00173] In a preferred embodiment, R1a is H.
[00174] Additional embodiments of the present invention are described below.
[00175] In one mode,

[00176] R1 = where
[00177] R1a = H or -CH3

[00178] or R1 = where
[00179] D = deuterium;
[00180] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[00181] R3 = H;
[00182] R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or
[00183] R4 = H, and R5 = -CH3 or -CH2OH, or
[00184] R4 = H or -CH3 and R5 = H OR -CH3;
[00185] or
[00186] R3 = H and R4 = H;
[00187] R2eR5 = - (CH2) 4-;
[00188] or
[00189] R4 = H and R5 = H; and
[00190] R2 = -CH2OH, and R3 = -CH3; or
[00191] R2 = H or -CH3, and R3 = -CH2OH, or a pharmaceutically acceptable salt thereof.
[00192] In another modality,
[00193] R1 =
on what
[00194] R1a = H or -CH3

[00195] or R1 = where
[00196] D = deuterium;
[00197] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[00198] R3 = H;
[00199] R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or
[00200] R4 = H, and R5 = -CH3 or -CH2OH, or
[00201] R4 = H or -CH3 and R5 = H or -CH3;
[00202] or
[00203] R4 = H and R5 = H; and
[00204] R2 = -CH2OH, and R3 = -CH3; or
[00205] R2 = H or -CH3, and R3 = -CH2OH, or a pharmaceutically acceptable salt thereof.
[00206] In an additional modality,

[00207] R1 = where
[00208] R1a = H or -CH3

[00209] or R1 =
[00210] where
[00211] D = deuterium;
[00212] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[00213] R3 = H;
[00214] R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or
[00215] R4 = H, and R5 = -CH3 or -CH2OH, or
[00216] R4 = H or -CH3 and R5 = H OR -CH3I or a pharmaceutically acceptable salt thereof.
[00217] In an additional modality,

[00218] R1 = where
[00219] R1a = H or -CH3
[00220] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[00221] R3 = H;
[00222] R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H θu
[00223] R4 = H, and R5 = -CH3 or -CH2OH, or
[00224] R4 = H or -CH3 and R5 = H or -CH3, or a pharmaceutically acceptable salt thereof.
[00225] In another modality,

[00226] R1 = where
[00227] R1a = H or -CH3
[00228] R2 = -CH3OU -CH2OH;
[00229] R3 = H;
[00230] R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or
[00231] R4 = H, and R5 = -CH3 or -CH2OH, or
[00232] R4 = H or -CH3 and R5 = H or -CH3, or a pharmaceutically acceptable salt thereof.
[00233] In another modality, preferably

[00234] R1 = where
[00235] R1a = H or -CH3
[00236] R2 = -CH3OU -CH2OH;
[00237] R3 = H;
[00238] R4 = -CH3, -CH2OH or -CH2CH2OH and R5 = H 0 (J
[00239] R4 = H and R5 = CH3 or -CH2OH, or a pharmaceutically acceptable salt thereof.
[00240] In another modality, preferably

[00241] R1 = where
[00242] R1a = H or -CH3
[00243] R2 = -CH3 or -CH2OH;
[00244] R3 = H;
[00245] R4 = -CH3 or -CH2CH2OH, and
[00246] R5 = H, or a pharmaceutically acceptable salt thereof.
[00247] In one mode,

[00248] R1 = where
[00249] R1a = H or -CH3
[00250] or R1 =
on what
[00251] D = deuterium;
[00252] R2 = _C | _ | 3-CH2OH, -CH2OCH3J -CH2CH2OH, -CH2OC (O) H;
[00253] R3 = H;
[00254] R4 = -CH3 OR -CH2OH, and R5 = H, OR
[00255] R4 = H, and R5 = -CH3 or -CH2OH, or
[00256] R4 = RS = H OR _CH3.
[00257] or
[00258] R3 = R4 = H
[00259] R2 and R5 = - (CH2) 4-;
[00260] or
[00261] R4 = R5 = H; and
[00262] R2 = -CH2OH, and R3 = -CH3; or
[00263] R2 = H or -CH3, and R3 = -CH2OH,
[00264] or a pharmaceutically acceptable salt thereof.
[00265] In another modality,
[00266] R1 =
on what
[00267] R1a = H or -CH3
[00268] or R1 =
on what
[00269] D = deuterium;
[00270] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2OC (O) H;
[00271] R3 = H;
[00272] R4 = -CH3 OR -CH2OH, and R5 = H, or
[00273] R4 = H, and R5 = -CH3 or -CH2OH, or
[00274] R4 = R5 = H or -CH3;
[00275] or
[00276] R4 = R5 = H: e
[00277] R2 = -CH2OH, and R3 = -CH3; or
[00278] R2 = H or -CH3, and R3 = -CH2OH, or a pharmaceutically acceptable salt thereof.
[00279] In an additional modality,

[00280] R1 = where
[00281] R1a = H or-CH3
[00282] or R1 =
on what
[00283] D = deuterium;
[00284] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2OC (O) H;
[00285] R3 = H;
[00286] R4 = -CH3OU -CH2OH, and R5 = H, or
[00287] R4 = H, and R5 = -CH3 or -CH2OH, or
[00288] R4 = R5 = H or -CH3, or a pharmaceutically acceptable salt thereof.
[00289] In an additional modality,
[00290] R1 =
on what
[00291] R1a = H or -CH3
[00292] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2OC (O) H;
[00293] R3 = H;
[00294] R4 = -CH3 or -CH2OH, and R5 = H, or
[00295] R4 = H, and R5 = -CH3 or -CH2OH, or
[00296] R4 = R5 = H or -CH3, or a pharmaceutically acceptable salt thereof.
[00297] In another modality,

[00298] R1 = where
[00299] R1a = H or -CH3
[00300] R2 = -CH3 or -CH2OH;
[00301] R3 = H;
[00302] R4 = -CH3 or -CH2OH, and R5 = H, or
[00303] R4 = H, and R5 = -CH3 or -CH2OH, or
[00304] R4 = R5 = H or -CH3, or a pharmaceutically acceptable salt thereof.
[00305] In another modality, preferably
[00306] R1 =
on what
[00307] R1a = H or -CH3
[00308] R2 = -CH3 or -CH2OH;
[00309] R3 = H;
[00310] R4 = -CH3 or -CH2OH and R5 = H or
[00311] R4 = H and R5 = CH3 or -CH2OH, or a pharmaceutically acceptable salt thereof.
[00312] In another modality, preferably

[00313] R1 = where
[00314] R1a = H or -CH3
[00315] R2 = -CH3 or -CH2OH;
[00316] R3 = H;
[00317] R4 = -CH3, and
[00318] R5 = H, or a pharmaceutically acceptable salt thereof.
[00319] In another preferred mode,
[00320] R1 =
on what
[00321] R1a = H or-CH3
[00322] R2 = -CH2OH;
[00323] R3 = H;
[00324] R4 = -CH3, and
[00325] R5 = H, or a pharmaceutically acceptable salt thereof.
[00326] In one embodiment, compounds with the following Formula (IA ') are provided:
wherein R1a, R2, R3, R4 and R5 are as described in any of the embodiments mentioned above.
[00327] In one embodiment, R1a can be hydrogen, thus providing compounds of the following Formula (IA):
on what
[00328] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[00329] R3 = H;
[00330] R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or
[00331] R4 = H, and R5 = -CH3 or -CH2OH, or
[00332] R4 = H or -CH3 and R5 = H or -CH3, or a pharmaceutically acceptable salt thereof.
[00333] In an embodiment of the compounds of Formula (IA),
[00334] R2 = -CH3OU -CH2OH;
[00335] R3 = H;
[00336] R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or
[00337] R4 = H, and R5 = -CH3 or -CH2OH, or
[00338] R4 = H or -CH3 and R5 = H or -CH3, or a pharmaceutically acceptable salt thereof.
[00339] In another embodiment of the compounds of Formula (IA),
[00340] R2 = -CH3OU -CH2OH;
[00341] R3 = H;
[00342] R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or
[00343] R4 = H, and R5 = -CH3 or -CH2OH or a pharmaceutically acceptable salt thereof.
[00344] In another embodiment of the compounds of Formula (IA),
[00345] R2 = -CH3 or -CH2OH;
[00346] R3 = H;
[00347] R4 = -CH3, -CH2OH or -CH2CH2OH, and
[00348] R5 = H or a pharmaceutically acceptable salt thereof.
[00349] In another embodiment of the compounds of Formula (IA),
[00350] R2 = -CH3;
[00351] R3 = H;
[00352] R4 = -CH2CH2OH, and
[00353] R5 = H or a pharmaceutically acceptable salt thereof.
[00354] Alternatively, in a modality where R1a can be hydrogen, compounds of the following Formula (IA) are provided:
on what,
[00355] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2OC (O) H;
[00356] R3 = H;
[00357] R4 = -CH3OU -CH2OH, and R5 = H, or
[00358] R4 = H, and R5 = -CH3 or -CH2OH, or
[00359] R4 = R5 = H or -CH3, or a pharmaceutically acceptable salt thereof.
[00360] In a modality of compounds of Formula (IA),
[00361] R2 = -CH3OU -CH2OH;
[00362] R3 = H;
[00363] R4 = -CH3OU -CH2OH, and R5 = H, or
[00364] R4 = H, and R5 = -CH3 or -CH2OH, or
[00365] R4 = R5 = H or -CH3, or a pharmaceutically acceptable salt thereof.
[00366] In another modality of compounds of Formula (IA),
[00367] R2 = -CH3OU -CH2OH;
[00368] R3 = H;
[00369] R4 = -CH3OU -CH2OH, and R5 = H, or
[00370] R4 = H, and R5 = -CH3 or -CH2OH, or a pharmaceutically acceptable salt thereof.
[00371] In another modality of compounds of Formula (IA),
[00372] R2 = -CH3 OR -CH2OH;
[00373] R3 = H;
[00374] R4 = -CH3 and
[00375] R5 = H or a pharmaceutically acceptable salt thereof.
[00376] In a preferred embodiment of compounds of Formula (IA),
[00377] R2 = -CH2OH;
[00378] R3 = H;
[00379] R4 = -CH3 and
[00380] R5 = H, or a pharmaceutically acceptable salt thereof.
[00381] Additional modalities (listed) are provided below: Mode 1.
[00382] A compound of Formula (I)
on what,

[00383] R1 = where
[00384] R1a = H or -CH3
[00385] or R1 =
on what
[00386] D = deuterium;
[00387] R2 = H and R3 = H;
[00388] R4 = H, and R5 = -CH3 or -CH2OH;
[00389] R4 = -CH2OH, and R5 = H; or
[00390] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[00391] R3 = H;
[00392] R4 = -CH3, -CH2OH, -CH2CH2OH, -CH2CH (OH) CH3OU - CH2C (OH) (CH3) 2 and R5 = H, or
[00393] R4 = H, and R5 = -CH3, -CH2OH, -CH2CH (OH) CH3 or - CH2C (OH) (CH3) 2, or
[00394] R4 = H or -CH3 and R5 = H or -CH3; or
[00395] R3 = H and R4 = H;
[00396] R2 and R5 are linked and form - (CH2) 4-; or
[00397] R4 = H and R5 = H; and
[00398] R2 = -CH2OH, and R3 = -CH3; or
[00399] R2 = H or -CH3, and R3 = -CH2OH; or
[00400] R2 = H and R4 = H; and
[00401] R3 and R5 are linked and form the group
or the group
or
[00402] R3 = H and R5 = H; and
[00403] R2 and R4 are linked and form the group
or a pharmaceutically acceptable salt thereof. Mode 2,
[00404] A compound according to Modality 1, in which
[00405] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[00406] R3 = H;
[00407] R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or
[00408] R4 = H, and R5 = -CH3 or -CH2OH, or
[00409] R4 = H or -CH3 and R5 = H OR -CH3;
[00410] or
[00411] R3 = H and R4 = H;
[00412] R2 and R5 = - (CH2) 4-;
[00413] or
[00414] R4 = H and R5 = H; and
[00415] R2 = -CH2OH, and R3 = -CH3; OR
[00416] R2 = H or -CH3, and R3 = -CH2OH,
[00417] or a pharmaceutically acceptable salt thereof. Mode 3.
[00418] A compound according to Modality 1 or Modality 2, in which
[00419] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[00420] R3 = H;
[00421] R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or
[00422] R4 = H, and R5 = -CH3 or -CH2OH, or
[00423] R4 = H or -CH3 and R5 = H or -CH3;
[00424] or
[00425] R4 = H and R5 = H; and
[00426] R2 = -CH2OH, and R3 = -CH3; or
[00427] R2 = H or -CH3, and R3 = -CH2OH,
[00428] or a pharmaceutically acceptable salt thereof. Mode 4.
[00429] A compound according to any of Modalities 1 to 3, in which,
[00430] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[00431] R3 = H;
[00432] R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or
[00433] R4 = H, and R5 = -CH3 or -CH2OH, or
[00434] R4 = H and R5 = -CH3 or -CH2OH or
[00435] R4 = H or -CH3 and R5 = H or -CH3, or a pharmaceutically acceptable salt thereof. Mode 5.
[00436] A compound according to any of Modalities 1 to 4, of Formula (IA ')
on what
[00437] R1a = H or -CH3, or a pharmaceutically acceptable salt thereof. Mode 6.
[00438] A compound according to Modality 1, of Formula (IA):
on what,
[00439] R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or -CH2OC (O) H;
[00440] R3 = H;
[00441] R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or
[00442] R4 = H, and R5 = -CH3 or -CH2OH, or
[00443] R4 = H or -CH3 and R5 = H or -CH3,
[00444] or a pharmaceutically acceptable salt thereof. Mode 7,
[00445] A compound according to Modality 6, in which,
[00446] R2 = -CH3OU -CH2OH;
[00447] R3 = H;
[00448] R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or
[00449] R4 = H, and R5 = -CH3 or -CH2OH, or
[00450] R4 = H or -CH3 and R5 = H OR -CH3,
[00451] or a pharmaceutically acceptable salt thereof. Mode 8,
[00452] A compound according to Modality 7, in which,
[00453] R2 = -CH3OU -CH2OH;
[00454] R3 = H;
[00455] R4 = -CH3, -CH2OH or -CH2CH2OH and R5 = H or
[00456] R4 = H and R5 = CH3 or -CH2OH,
[00457] or a pharmaceutically acceptable salt thereof. Mode 9.
[00458] A compound according to Modality 8, in which
[00459] R2 = -CH3OU -CH2OH;
[00460] R3 = H;
[00461] R4 = -CH3OU -CH2CH2OH and
[00462] R5 = H,
[00463] or a pharmaceutically acceptable salt thereof. Mode 10,
[00464] A compound or a pharmaceutically acceptable salt thereof, according to Mode 1, which is selected from among
[00465] (S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-methyl-oxazolidin-2-one ,
[00466] (S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-hydroxymethyl-5,5-dimethyl -oxazolidin-2-one,
[00467] racemic 3- (2'-amino-2-morpholino-4 '- (trifluormethyl) -4,5'-bipyrimidin-6-yl) - 4- (hydroxymethyl) -4-methyloxazolidin-2-one,
[00468] (S) -3- (2'-amino-2-morpholino-4 '- (trifluormethyl) -4,5'-bipyrimidin-6-yl) -4- (hydroxymethyl) -4-methyloxazolidin-2- ona (absolute stereochemistry not determined),
[00469] (R) -3- (2'-amino-2-morpholino-4 '- (trifluormethyl) -4,5'-bipyrimidin-6-yl) -4- (hydroxymethyl) -4-methyloxazolidin-2- ona (absolute stereochemistry not determined),
[00470] (3aS, 7aS) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -hexa-hydro-benzoxazole-2 -one,
[00471] (S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-methoxymethyl-oxazolidin-2-one ,
[00472] (4S, 5S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-hydroxymethyl-5-methyl -oxazolidin-2-one,
[00473] (S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-hydroxymethyl-oxazolidin-2-one ,
[00474] (4S, 5R) -3- (2'-Amino-2- (D8-morpholin-4-yl) -4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-hydroxymethyl -5-methyl-oxazolidin-2-one,
[00475] (S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4- (2-hydroxy-ethyl) -oxazolidin-2-one,
[00476] (4S, 5R) -3- [2'-Amino-2 - ((S) -3-methyl-morpholin-4-yl) -4'- trifluormethyl- [4,5 '] bipyrimidinyl-6- yl] -4-hydroxymethyl-5-methyl-oxazolidin-2-one,
[00477] (4S, 5R) -3- (2'-amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -5-methyl-2- oxo-oxazolidin-4-ylmethyl formic acid,
[00478] (S) -3- [2'-Amino-2 - (((S) -3-methyl-morpholin-4-yl) -4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl] -4-methyl-oxazolidin-2-one,
[00479] (S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -5-hydroxymethyl-oxazolidin-2-one ,
[00480] (4S, 5R) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -5-hydroxymethyl-4-methyl -oxazolidin-2-one,
[00481] (S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -5-methyl-oxazolidin-2-one ,
[00482] (S) -3- (2'-amino-2-D8-morpholino-4 '- (trifluormethyl) - [4,5'- bipyrimidin] -6-yl) -4-methyloxazolidin-2-one,
[00483] (4S, 5R) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-hydroxymethyl-5-methyl -oxazolidin-2-one,
[00484] (4S, 5S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -5-hydroxymethyl-4-methyl -oxazolidin-2-one,
[00485] (R) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -5-hydroxymethyl-oxazolidin-2-one ,
[00486] (3aR, 6aR) -3- (2'-amino-2-morpholino-4 '- (trifluormethyl) - [4,5'- bipyrimidin] -6-yl) tetrahydrofuro [3,4-d] oxazole -2 (3H) -one,
[00487] (3aR *, 6R *, 6aR *) - 3- (2'-Amino-2-morpholino-4 '- (trifluormethyl) - [4,5'-bipyrimidin] -6-yl) -6-hydroxyhexa -hydro-2H-cyclopenta [d] oxazole-2-one racemic,
[00488] (3aR, 6R, 6aR) - (2'-Amino-2-morpholino-4 '- (trifluormethyl) - [4,5'- bipyrimidin] -6-yl) -6-hydroxyhexa-hydro-2H- cyclopenta [d] oxazol-2-one,
[00489] (3aS, 6S, 6aS) - (2'-Amino-2-morpholino-4 '- (trifluormethyl) - [4,5'- bipyrimidin] -6-yl) -6-hydroxyhexa-hydro-2H- cyclopenta [d] oxazol-2-one, and
[00490] (4S, 5R) -3- (2'-Amino-2-morpholino-4 '- (trifluormethyl) - [4,5'- bipyrimidin] -6-yl) -5- (2-hydroxyethyl) - 4-methyloxazolidin-2-one. Mode 11.
[00491] A compound or a pharmaceutically acceptable salt thereof, according to Mode 1 which is selected from (4S, 5R) -3- [2'-Amino-2 - ((S) -3-methyl-morpholin-4 -yl) -4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl] -4-hydroxymethyl-5-methyl-oxazolidin-2-one, (4S, 5R) -3- (2'-Amino- 2- morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-hydroxymethyl-5-methyl-oxazolidin-2-one and (4S, 5R) -3- (2 '-Amino-2-morpholino-4' - (trifluormethyl) - [4,5'-bipyrimidin] -6-yl) -5- (2-hydroxyethyl) -4-methyloxazolidin-2-one. Mode 12.
[00492] A compound that is selected from (4S, 5R) -3- [2'-Amino-2 - ((S) -3-methyl-morpholin-4-yl) -4, -trifluormethyl- [4,5 '] bipyrimidinyl-6-yl] -4-hydroxymethyl-5-methyl-oxazolidin-2-one,
[00493] (4S, 5R) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-hydroxymethyl-5-methyl -oxazolidin-2-one, and (4S, 5R) - 3- (2'-Amino-2-morpholino-4 '- (trifluormethyl) - [4,5'-bipyrimidin] -6-yl) -5- ( 2-hydroxyethyl) -4-methyloxazolidin-2-one. Mode 13.
[00494] The compound (4S, 5R) -3- (2'-Amino-2 - ((S) -3-methyl-morpholin-4-yl) -4'-trifluormethyl- [4,5 '] bipyrimidinyl- 6-yl] -4-hydroxymethyl-5-methyl-oxazolidin-2-one. Mode 14.
[00495] Compound (4S, 5R) -3- (2'-Amino-2-morpholino-4-yl-4'-trifluormethyl- [4,5'-bipyrimidinyl] -6-yl) -4-hydroxymethyl) -5-methyl-oxazolidin-2-one. Mode 15.
[00496] The compound (4S, 5R) -3- (2'-Amino-2-morpholino-4'- (trifluormethyl) - [4,5'-bipyrimidin] -6-yl) -5- (2-hydroxyethyl ) -4-methyloxazolidin-2-one.
[00497] A pharmaceutically acceptable salt of the compound of Mode 13, Mode 14 or Mode 15.
[00498] In another aspect of the present invention, a crystalline form of the compound obtained from Example 10 is provided which has an X-ray diffraction spectrum substantially equal to the X-ray powder diffraction spectrum shown in Figure 2.
[00499] In another aspect of the present invention, a crystalline form of the compound obtained from Example 18, batch A is provided which has an X-ray diffraction spectrum substantially equal to the X-ray powder diffraction spectrum shown in Figure 4 .
[00500] In another aspect of the present invention, a crystalline form of the compound obtained from Example 18, batch B is provided which has an X-ray diffraction spectrum substantially equal to the X-ray powder diffraction spectrum shown in Figure 6 .
[00501] In another aspect of the present invention, a crystalline form of the compound obtained from Example 18, batch C is provided which has an X-ray diffraction spectrum substantially equal to the X-ray powder diffraction spectrum shown in Figure 8 .
[00502] In another aspect of the present invention, a crystalline form of the compound obtained from Example 18, batch D is provided which has an X-ray diffraction spectrum substantially equal to the X-ray powder diffraction spectrum shown in Figure 10 .
[00503] In another aspect of the present invention, a crystalline form of the compound obtained from Example 18, batch E is provided which has an X-ray diffraction spectrum substantially equal to the X-ray powder diffraction spectrum shown in Figure 12 .
[00504] The expression "essentially equal" with respect to the peak positions of X-ray diffraction means that the peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that peak positions (20) will show some variability between devices, typically at a maximum of 0.2 °. Additionally, one skilled in the art will appreciate that the relative peak intensities will show variability between devices as well as variability due to the degree of crystallinity, preferred orientation, prepared sample surface and other factors known to those skilled in the art and should be taken as a measure only. qualitative.
[00505] Specific modalities are provided by the specific exemplifying compounds described herein.
[00506] The present invention provides compounds and pharmaceutical formulations thereof which are useful in the treatment of diseases, conditions and / or disorders in which PI3K contributes to the pathogenesis of the disease described herein.
[00507] The compounds of the present invention can be synthesized by synthetic routes that include processes analogous to those well known in chemical techniques, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) Or are readily prepared using methods well known to those skilled in the art (for example, prepared by the methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, volumes 1-19, New York (1967-1999 ed.) Or Beilsteins Handbuch der organischem Chemie, 4, Aufl. Ed. Springer-Verlag, Berlin, including supplements (also available through the bank Beilstein online database)).
[00508] For illustrative purposes, the reaction schemes described below provide potential pathways for the synthesis of compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the inventive compounds. Although specific starting materials and reagents are illustrated in the diagrams and discussed below, other starting materials and reagents can be easily replaced to provide a variety of derivatives and / or reaction conditions. In addition, several of the compounds prepared by the methods described below can be further modified in light of that description using conventional chemistry well known to those skilled in the art.
[00509] In the preparation of compounds of the present invention, protection of remote functionality (e.g., primary and secondary amino groups, hydroxyl and carboxyl) from intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino protecting groups (NH-Pg) include acetyl, trifluorocetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Suitable protective hydroxyl groups include trialkylsilyl ethers where one or two of the alkyl groups can be replaced by phenyl. Suitable carboxyl protecting groups (C (O) O-Pg) include alkyl esters (for example methyl, ethyl or t-butyl), benzyl esters, silyl esters and the like. The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
[00510] Scheme 1 (below) describes a potential pathway for the production of compounds of Formula (IA '), where R1-R5 are as defined above. In cases where a protecting group is present, a deprotection step is added to convert 'protected AI to AI'.
Layout 1
[00511] Alternatively, the compounds of Formula (IA ') can also be synthesized by reversing the steps shown in scheme I, that is, Suzuki coupling first, followed by Buchwald reaction with lb.
[00512] For those oxazolidine-2-ones lb that are not commercially available, Scheme 2 below provides a process for the preparation of said intermediates where R2-R5 are as defined above. If a primary hydroxyl group is present in R2 to R5, a selective protection step is preceded as exemplified in Scheme 3. The amino group can be protected in a preceding step as shown in Scheme 4, where a different hydroxyl protecting group is also is shown.
Layout 2
Layout 3
Layout 4
[00513] The protected product of Scheme 3 can be cyclized with triphosgene as generally shown in Scheme 2 and, specifically, shown in Scheme 5 to provide an example of an intermediary lb.
Layout 5
Layout 6
[00514] The double protected product of Scheme 4 can be cleaved with sodium hydrate as shown in Scheme 6 to provide an example of an intermediary lb.
[00515] Scheme 7 illustrates an alternative route to the doubly protected intermediate of Scheme 4, which can then be cyclized as already shown in Scheme 6.
Layout 7
[00516] Scheme 8 below provides the synthesis of the boronic ester of intermediate B.
Layout 8
[00517] The reaction of the cyclized product from Scheme 6 with the intermediate 4,6-dichloro-pyrimidine (for example, intermediate A or the product from step 10.1, both referred to here below) as shown in Scheme 1, can provide intermediates additional and specific ones are shown below:

[00518] The subsequent reaction of the intermediates formed as shown in Scheme 1 with the intermediate B, provides a protected product IA ', as follows:

[00519] Therefore, an intermediate compound of the invention includes a compound with the following Formulas:

[00520] Where R1a and R4 are as previously defined here, Hal is halogen, just like chlorine and PG is a protecting group, for example, a silyl protecting group that forms, for example, trialkylsilyl ethers, where one or two of the alkyl groups can be substituted by phenyl, for example, an alkyl-diphenylsilyl ether protecting group, specifically dimethyl-tert-butylsilyl or diphenyl-tert-butylsilyl.
[00521] Another intermediate compound of the invention includes a compound of the following Formulas:

[00522] Other intermediate compounds similarly protected as illustrated here above can be predicted with reference to the Formulas thereof, if a primary hydroxyl group is present in R2 to R5. Such protected compounds are also included in the description. For example, where R4 is the -CH2CH2OH group, it can be protected to provide compounds where R4 is -CH2CH2O-PG, where PG is as defined above, for example:

[00523] Deprotection of the protected hydroxyl group of tertiary butyldiphenylsilyl or tertiary butyldimethylsilyl (general deprotection of silyl ethers) of the protected IA 'product to provide, for example, the final product, can be obtained using HF.piridine (eg in THF) or HCI.
[00524] The compounds of the present invention or the intermediates used here can be isolated and used as the compound per se (eg, free base form) or as its salt, if for example, the pKA value of the compound is such that allow salt to form. As used herein, the terms "salt" or "salts" refer to an acid addition or basic addition salt of a compound of the invention. "Salts" include, in particular, "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological efficacy and properties of the compounds of that invention and that are typically not biologically or otherwise undesirable. The compounds of the present invention may be able to form acid addition salts by virtue of the presence of the amino group. Compounds of the invention are preferred.
[00525] Inorganic acids and organic acids for the formation of pharmaceutically acceptable acid addition salts include, for example, acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camforsulfate salts. , chloride / hydrochloride, chlorophyllonate, citrate, ethanisulfonate, fumarate, gluceptate, gluconate, glucuronate, hypurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, mesylate, mesylate, mesylate, mesylate , napsylate, ni-cotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, pro-pionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifl.
[00526] Inorganic acids for salt derivation include, for example, hydrochloric acid, propionic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
[00527] Organic acids for salt derivation include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid and the like. Pharmaceutically acceptable basic addition salts can be formed with inorganic and organic bases.
[00528] Inorganic bases for salt derivation include, for example, ammonia salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts can be derived from sodium, potassium, ammonia, calcium, magnesium, iron, silver, zinc and copper; particularly suitable salts include ammonia, potassium, sodium, calcium and magnesium salts.
[00529] Organic bases for salt derivation include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, ion exchange resins and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
[00530] In the case where the pharmaceutically acceptable salts of the present invention can be formed, they can be synthesized from a parent compound, a basic or acidic portion, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg or K hydroxide, carbonate or bicarbonate or the like) or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or an organic solvent or a mixture of the two. Generally, the use of a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
[00531] Unless otherwise stated, any Formula given here is intended to represent unmarked forms. Isotopically labeled forms of the compounds with deuterium are shown with deuterium (D) as a substituent in place of H. Other isotopically labeled compounds of the present invention can be prepared and have the structures illustrated by the Formulas given here except that one or more atoms are replaced by an atom that has a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, "C, 13C, 14C, 15N, 18F 31P, 32P, 35S, 36CI, 125l, respectively. The invention may include various isotopically labeled compounds as defined herein, for example, those in which radioactive isotopes, such as 3H, 13C 6 14C are present. Such isotopically labeled compounds are useful in metabolic studies (with 14C), reaction kinetics studies (with, for example, 2H or 3H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission tomography (SPECT) including distribution of drug or substrate in tissue or in patients undergoing radiation treatment In particular, 18F or a labeled compound may be particularly desirable for PET or SPECT studies. m be prepared in general by carrying out the procedures described in the schemes or in the examples and preparations described below, by replacing an available isotopically labeled reagent with a non-isotopically labeled reagent, for example, deuterium-labeled morpholino (D8-morpholino) .
[00532] In addition, substitution with heavier isotopes, particularly deuterium (ie 2H or D) can provide certain therapeutic advantages that result from greater metabolic stability, for example, increased in vivo half-life, need for reduced dosage, reduced CYP inhibition (competitive or time-dependent) or an improvement in the therapeutic index. For example, substitution with deuterium can modulate undesirable side effects of the non-deuterated compound, such as competitive CYP inhibition, time-dependent CYP inactivation, etc. it is understood that deuterium in this context is considered as a substituent on the compounds of the present invention. The concentration of such a heavy isotope, specifically deuterium, can be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used here means the ratio between the isotopic abundance and the natural abundance of a specific isotope. If a substituent on a compound of this invention is indicated as deuterium, that compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation in each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation) ), or at least 6633.3 (99.5% deuterium incorporation).
[00533] In addition, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water). Such solvent molecules are also those commonly used in the pharmaceutical technique, which are known to be harmless to the recipient, for example, water, ethanol and the like. The term "hydrate" refers to the complex where the solvent molecule is water. The term "solvent" refers to a molecular complex of a compound of the present invention (including its pharmaceutically acceptable salts) with one or more solvent molecules incorporated into the crystalline lattice structure. The solvent molecules in the solvate can be present in a regular arrangement and / or an unordered arrangement. The solvate may comprise a stoichiometric or non-stoichiometric amount of the solvent molecules. For example, a solvate with a non-stoichiometric amount of solvent molecules can result from the partial loss of solvent from the solvate. Solvents can occur as dimers or oligomers that comprise more than one molecule or compound according to the present invention, within the crystalline lattice structure.
[00534] The compounds of the present invention including their salts, hydrates and solvates can inherently or by design form polymorphs.
[00535] As used here, "polymorph" refers to crystalline forms that have the same chemical composition, but different spatial arrangements of the molecules, atoms and / or ions that form the crystal.
[00536] As used here, "amorphous" refers to a solid form of the molecule, atom and / or ions that is not crystalline. An amorphous solid does not show a definitive pattern in X-ray diffraction.
[00537] Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, de-acetone, de-DMSO.
[00538] It will be recognized by those skilled in the art that the compounds of the present invention contain chiral centers and as such exist in isomeric forms. As used here, the term "isomers" refers to different compounds that have the same molecular formula, but differ in the arrangement and configuration of the atoms. Also as used herein, the term "an optical isomer" or a "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present invention. It is understood that a substituent can be coupled to a chiral center of a carbon atom. Therefore, the compounds of the invention include enantiomers, shown by the stereospecific arrangements indicative at chiral centers in the structural description of the compounds of the invention, in which a broken wedge bond indicates the coupled substituent or that the atom is below the plane and a solid wedge bond indicates the coupled substituent and the atom is above the plane.
[00539] "Enantiomers" are a pair of stereoisomers that are not mirror images superimposed on each other. A 1: 1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to designate a racemic mixture where appropriate.
[00540] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but that are not mirror images of each other.
[00541] The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon can be specified by R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-), depending on the direction (dextro or levorotatory) in which they rotate in the plane of polarized light at the wavelength of the sodium D line. Some compounds described here may contain one or more asymmetric centers or axes and can thus give rise to enantiomers, diastereoisomers and other stereoisomeric forms that can be defined in terms of absolute stereochemistry, such as (/ ) - or (S) -.
Any asymmetric atom (e.g., chiral carbon or the like) of the compounds of the present invention can be enantiomerically enriched, for example, the (/ ) - or (S) - configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess or at least 99% enantiomeric excess in the configuration (/ ) - or (S) - described for the specific asymmetric atom (for example, chiral carbon).
[00543] Consequently, a compound of the present invention can be in the form of a substantially pure enantiomer.
[00544] Any resulting mixtures of isomers can be separated based on the physical-chemical differences of the constituents, in the pure or substantially pure optical isomers, for example, by chromatography and / or fractional crystallization.
[00545] Optically active (/ ) - and (S) - isomers can be prepared using chiral syntones or chiral reagents or resolved using conventional techniques. Any racemate resulting from final or intermediate products can be resolved in the optical antipodes by known methods. For example, known methods include separating the diastereoisomeric salts thereof, obtained with an optically active acid or base and releasing the optically active acid or basic compound. In particular, a basic portion can then be employed to resolve the compounds of the present invention into their optical antipodes, for example, by fractional crystallization of a salt formed with an optically active acid, for example, tartaric acid, dibenzoyl tartaric acid, di-O, O'-p-toluoil tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, for example, high pressure liquid chromatography (HPLC) using a chiral absorber.
[00546] If the compound contains a double bond, the substituent can have the E or Z configuration. If the compound contains a di-substituted cycloalkyl, the cycloalkyl substituent can have a cis or trans configuration. All tautomeric forms are also intended to be included.
[00547] Compounds of the invention that contain groups capable of acting as donors and / or acceptors for hydrogen bonds may be able to form crystals with suitable cocrystal builders. Such cocrystals can be prepared from compounds of the present invention by known cocrystal forming procedures. Such procedures include grinding, heating, cosublimation, cofusion or contacting the solution compounds of the present invention with the cocrystal former under conditions of crystallization and isolation of the cocrystals formed in this manner. Suitable cocrystal builders include those described in WO 2004/078163. Therefore, the invention further provides co-crystals that comprise a compound of the present invention.
[00548] The compounds of Formula (I) inhibit PI3 kinases (PIK3) and can therefore be useful in the treatment of protein or lipid kinase dependent diseases, especially diseases that depend on PI3 class I kinases, PI3Kalfa, PI3Kbeta, PI3Kdelta and PI3Kgama or one or more individual kinase members or any combination of any two or more of the aforementioned kinases.
[00549] Compounds that inhibit the activity of more than one of the PI3K Class I isoforms (alpha, beta, delta and gamma), in particular substantially equipotent to the Class IA members p110a, p110b and p110d and optionally as well as the member of the Class IB p110g, are considered to be beneficial because such compounds are considered to have the ability to avoid adaptation mechanisms due to reactivation of the pathway through other isoforms, compared to compounds with unique specificity, for example, specificity by a member of the family of PI3K Class I. By "equipotent" is meant that the compounds inhibit various isoforms to a comparable extent, for example, as measured in an enzymatic or cellular assay described herein.
[00550] The increased inhibition potency of at least one of the PI3K isoforms (for example, inhibiting at least one PI3K isoform at lower concentrations) can be advantageous. In the case of null tumors for PTEN, for example, although the targeting isoform is p110b, complete efficacy may require the participation of other Class IA isoforms. For example, the potency on the alpha and beta isoforms can be advantageous.
[00551] There is also a need for compounds that potentially inhibit PI3Kalfa kinase, for example, for the treatment of cancers that are primarily targeted by the oncogenic forms of the gene encoding p110a (for example, PIK3CA H1047R or E545K), as well as tumors showing an increased copy number of PIK3CA.
[00552] It is desirable that the compounds of the present invention exhibit the mentioned PI3 kinase activity without showing activity on mTOR or at least exhibit a favorable selectivity to inhibit one or more of the Class I PI3 Kinases on mTOR. For example, compounds that show selective inhibition in favor of one or more isoforms of PI3K (for example, at least two, preferably three, for example, the alpha, beta and delta isoforms) compared with mTOR are desirable, because the inhibitory effect of mTOR generally reduces the safety window, most especially when the compound inhibits mTOR more sharply than PI3K (unfavorable proportion).
[00553] Additionally, PI3K inhibitors that have a reduced off-target effect or do not have an off-target effect, such as those that have no binding to tubulin, are desired, since such an effect can cause unconnected toxicity effects with the inhibition of PI3K in the target and, therefore, such compounds may require additional careful dosage control to ensure that the therapeutic effect is controllable and attributable to the inhibition of PI3K. The compounds of the present invention, when measured using the procedures described herein, show a weak or unobservable off-target effect (binding to tubulin).
[00554] Compounds that inhibit the activity of more than one of the PI3K Class I isoforms (alpha, beta, delta and gamma), in particular, substantially equipotent with the Class IA p110a, p110b and p110d members, as well as optionally with the Class IB p110g member and which additionally have a reduced off-target effect or have no off-target effect, such as having no tubulin binding or reduced tubulin binding, are desired.
[00555] The compounds desirably have an improved inhibition of at least one (for example, PI3Kalfa), but especially two (for example, PI3Kalfa and PI3Kbeta) or three (for example, PI3Kalfa, PI3Kbeta and PI3Kgama) as well as reduced off-target effect (in particular, an absence of) (eg, reduced or absent tu-bulin binding) are sought. Desirably, these compounds also show selective inhibition in favor of one or more isoforms of PI3K (for example, at least two, preferably three, for example, of the alpha, beta and delta isoforms) compared with mTOR, are desirable.
Consequently, in a further aspect, a compound of the present invention can be used (for example, in the manufacture of a medicament) for the treatment of diseases, conditions or disorders associated with the inhibition or antagonism of PI3K kinases in an individual ( for example, a mammal, preferably a human). Due to the relevance of PI3 kinase inhibition, the compounds of the present invention are therefore considered useful in the treatment of proliferative diseases such as cancer. Particular conditions / diseases for treatment by the compounds of the present invention include a benign or especially malignant tumor, solid tumors, a carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach (especially gastric tumors), esophagus, ovaries , colon, rectum, thyroid, sarcoma, glioblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a head and neck tumor, other diseases such as Cowden syndrome, LHermitte-Duclos disease and syndrome Bannayan-Zonana (or diseases in which the PI3K / PKB pathway is aberrantly activated), prostate hyperplasia, a neoplasm, especially epithelial in character, preferably breast carcinoma or squamous cell carcinoma, B cell malignancies such as leukemia chronic lymphocytic (LLC), non-Hodgkin's lymphoma (NHL), plasma cell myeloma and Hodgkin's lymphoma (LH) or a leukemia. The compounds are capable of desirably causing the regression of tumors and preventing the formation of tumor metastases and the growth of (micro) metastases. It may be possible to use the compounds of Formula (I) also in the treatment of diseases of the immune system insofar as several, or especially, individual lipid kinases and / or serine / threonine protein kinases (additional) are involved.
[00557] As used herein, the expression "one", "the" and similar expressions used in the context of the present invention (especially in the context of the claims) should be considered to encompass the singular and the plural unless otherwise indicated. otherwise or clearly contradicted by the context.
[00558] All methods described here can be performed in any appropriate order, unless otherwise indicated or clearly contradicted by the context. The use of any and all examples or exemplary language (for example, "such as") provided herein is intended merely to better illustrate the invention and not to impose a limitation on the scope of the claimed invention differently.
[00559] The compounds of the present invention are typically used as a pharmaceutical composition (for example, a compound of the present invention and at least one pharmaceutically acceptable carrier).
Therefore, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
[00561] A compound of the present invention can be supplied in an amorphous composition. A compound of the present invention can be supplied in a composition in its free form, that is, not in the form of a salt (the free base form). A compound of the present invention can be supplied in a composition in its free form, that is, not in the form of a salt (the form of free base) and also be in amorphous form.
[00562] As used herein, the term "pharmaceutically acceptable carrier" includes generally recognized as safe (GRAS) solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, antibacterial agents, antifungal agents), isotonic agents, agents that delay absorption, salts, preservatives, drug stabilizers, binders, excipients, disintegrating agents, lubricants, sweetening agents, flavoring agents, dyes, buffering agents (eg maleic acid, tartaric acid, lactic acid , citric acid, acetic acid, sodium bicarbonate, sodium phosphate and the like) and the like and combinations thereof, as will be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th. Ed. Mack Printing Company, 1990 , pp 1289-1329). Except, to the extent that any conventional vehicle is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated. For the purposes of this invention, solvates and hydrates are considered pharmaceutical compositions that comprise a compound of the present invention and a solvent (i.e., solvate) or water (i.e., a hydrate).
[00563] Formulations can be prepared using conventional dissolving and mixing procedures. For example, the concentrate of the drug substance (i.e., the compound of the present invention or the stabilized form of the compound (for example, a complex with a cyclodextrin derivative or other known complexing agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above The compound of the present invention is typically formulated in pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handled product.
[00564] The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration and rectal administration etc. In addition, the pharmaceutical compositions of the present invention can be made in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories) or in a liquid form (including without limitation, solutions, suspensions or emulsions). Pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain inert diluents, lubricating agents or conventional buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers etc.
[00565] Typically, pharmaceutical compositions are tablets or gelatin capsules that comprise the active ingredient together with:
[00566] a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;
[00567] b) lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salt and / or polyethylene glycol; for tablets too
[00568] c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired
[00569] d) disintegrants, for example, starches, agar, alginic acid or its sodium salt or effervescent mixtures; and / or
[00570] e) absorbents, dyes, flavorings and sweeteners.
[00571] The tablets can be coated with film or enteric coated according to methods known in the art.
[00572] Active ingredient solutions and also suspensions and, in particular, isotonic aqueous solutions or suspensions can be used, this being possible, for example, in the case of lyophilized compositions comprising the active ingredient alone or together with a vehicle, for example example, mannitol, for such solutions or suspensions to be produced before use. The pharmaceutical compositions can be sterilized and / or can comprise adjuvants, for example, preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating osmotic pressure and / or buffers; and they are prepared in a manner known per se, for example, by means of conventional dissolving or freeze-drying processes. Said solutions or suspensions can comprise substances that increase viscosity, such as sodium carboxymethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, dextran, polyvinylpyrrolidone or gelatin.
[00573] Oil suspensions comprise vegetable oil, synthetic or semi-synthetic oils routinely for injection purposes. As such, in particular, esters of liquid fatty acid which contain as an acid component a long-chain fatty acid having between 8 to 22 carbon atoms, especially between 12 to 22 carbon atoms, for example lauric acid, tridecyl acid , myristic acid, pentadecylic acid, palmitic acid, marginal acid, stearic acid, arachidic acid, beenic acid or corresponding unsaturated acids, for example, oleic acid, elaidic acid, erucic acid, brasidic acid or linoleic acid, if desired with addition of antioxidants, for example, vitamin E, beta-carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters has a maximum of 6 carbon atoms and is a mono- or polyhydroxy alcohol, for example, mono, di or trihydroxy-alcohol, for example, methanol, ethanol, propanol, butanol or pentanol; or the isomers of these, but especially glycol and glycerol. The following examples of fatty acid esters should therefore be mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethylene glycerol trioleate, Gattefossé, Paris), "Miglyol 812" (triglyceride of saturated fatty acids with a C8-C12 chain extension, Hüls AG, Germany), but especially vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybeans and more especially peanut oil.
[00574] Injectable compositions are usually prepared under sterile conditions; the same also applies to the introduction of the compositions in ampoules or vials and the sealing of the containers.
[00575] Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid vehicles, if desired, granulating the resulting mixture and processing the mixture, if desired or necessary, after the addition of appropriate excipients, in tablets, nuclei of dragees or capsules. It is also possible that they are incorporated into plastic vehicles that allow the active ingredients to diffuse or be released in measured quantities.
[00576] Compositions suitable for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. The tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. Such excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets are not coated or are coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period. For example, a delayed-acting material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin or as soft gelatin capsules, in which the active ingredient it is mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil.
[00577] Pharmaceutical compositions for topical administration can be obtained by combining the active ingredient with a liquid carrier (for example, an aqueous liquid carrier) to dissolve or disperse the asset, along with optional formulation ingredients such as solvents / solubilizers, agents gelling agents, oils, stabilizers, buffers and preservatives to provide, for example, a solution, lotion, cream, gel or ointment. The pharmaceutical composition for topical administration can be provided, for example, for dermal application. Pharmaceutical compositions for topical administration may comprise between approximately 0.1% to approximately 2% of the active ingredient, the active ingredient being especially a compound of Formula (I), in particular, a compound described in the individual examples thereof.
[00578] The pharmaceutical composition (or formulation) for application can be packaged in a variety of ways depending on the method used for administering the drug. Generally, an article for distribution includes a container that has the pharmaceutical formulation deposited in it in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as vials (of plastic or glass), ampoules, plastic bags, metal cylinders and the like. The container may also include a tamper-proof assembly to prevent indiscriminate access to the contents of the package. In addition, the container has a label on it that describes the contents of the container. The label can also include the appropriate warnings.
[00579] The pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention can be formulated for use as a parenteral administration. Pharmaceutical compositions (for example, intravenous formulation (iv)) may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional inert diluents or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers well known to those skilled in the art.
[00580] The present invention provides anhydrous pharmaceutical compositions and dosage forms that comprise the compounds of the present invention as active ingredients, since water can facilitate the degradation of certain compounds. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous ingredients or containing low humidity and low humidity conditions. An anhydrous pharmaceutical composition can be prepared and stored such that its anhydrous nature is maintained. Consequently, anhydrous compositions are packaged using known materials to prevent exposure to water such that they can be included in suitable prescription kits. Examples of suitable packaging include, but are not limited to, hermetically sealed aluminum packaging, plastics, unit-dose containers (eg bottles), blister packs and strip packs.
[00581] The invention further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate at which the compound of the present invention as an active ingredient will be decomposed. Such agents, which are referred to herein as "stabilizers" include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or salt buffers, etc.
[00582] A compound of the present invention, in particular, a compound described in the individual examples thereof, can be provided in an amorphous form.
[00583] A compound of the present invention, in particular, a compound described in the individual examples thereof, can be formulated as a standard suspension, nanosuspension and solid dispersion, for example, as follows. Standard Suspension:
[00584] 1) The necessary amount of the crystalline material of Example 18, Lot E was weighed in order to reach a concentration of the formulation of 3 mg / mL.
[00585] 2) The crystalline material of Example 18, Lot E was then dispersed in 0.5% [w / w] Carboxymethylcellulose / 0.5% [w / w] Tween 80 / Water.
[00586] 3) The suspension was centrifuged to homogenize.
[00587] 4) The suspension was sonicated using a sonicator to reduce the particle size (2 min). Nanosuspension
[00588] 1) 32 mg of crystalline material from Example 18, Lot E, precisely weighed in a custom made marble grinding device.
[00589] 2) 2,148 g of 0.2 mm zirconia grinding media were added to the grinding device
[00590] 3) 0.608 mL of HPMC 603 1% [w / V) (Hydroxypropylmethylcellulose grade 603) / SDS 0.05% (Sodium Dodecyl Sulphate) / Water were added to the grinding device
[00591] 4) The grinding devices were closed and placed in a rotary mill
[00592] 5) The sample was ground for 4 h at 400 rpm
[00593] 6) The nanosuspension was collected using a syringe Solid Dispersion
[00594] 1) 30 mg of the crystalline material of Example 18, Lot E were weighed in a lyophilization vial
[00595] 2) 30 mg of HPMC 603 (Hydroxypropylmethylcellulose grade 603) were added to the same vial
[00596] 3) 5.6 ml of Dioxane were added to the same vial. The bottle was closed with a lid.
[00597] 4) The sample was stirred in ambient conditions for 12 h
[00598] 5) The solution obtained was lyophilized according to the following conditions

[00599] When providing a compound of the invention as a solid dispersion, prepared, for example, by combining the compound with a carrier (such as a polymer, for example, HPMC) and solvent and lyophilizing the mixture (with the intention of providing the compound in amorphous form instead of crystalline form), for reasons of stability it may be advantageous to increase the ratio of the amount of vehicle to the amount of compound to avoid recrystallization of the compound when at rest.
[00600] In certain substances, it may be advantageous to administer the compound of the present invention in combination with at least one additional pharmaceutical (or therapeutic) agent (for example, an antiproliferative or anticancer agent or adjunct therapy typically used in chemotherapy). The compound of the present invention can be administered simultaneously with, before or after one or more other therapeutic agents. Alternatively, the compound of the present invention can be administered separately, by the same or a different route of administration, or together in the same pharmaceutical composition as the other agents. Additional suitable anticancer agents include, but are not limited to:
[00601] HER2 and HER3 receptor inhibitors: As recently exemplified in HER2 positive breast cancer models, PI3K inhibition will lead to reactivation of the pathway through FoxO-dependent HER2 / HER3 transcriptional induction, which implies in use of HER2 inhibitors in this context (Serra et al, 2011 Oncogene 30; Chandarlapaty et al, 2011 Cancer Cell 19; Chakrabarty et al 2012, PNAS 109). For example, Trastuzumab (sold under the trade name Herceptin® by Genetech / Roche), pertuzumab (sold under the trade name Perjeta ™ by Genetech / Roche), the drug-antibody conjugate Trastuzumab Emtanosine (T- DM1) from Genetech / Roche, erlotinib (sold under the trade name Tarceva® by Genetech / Roche), gefitinib (sold under the trade name Iressa ™ by AstraZeneca), MOR10703, neratinib (also known as HKI-272, (2E ) -N- [4 - [[3-chloro-4 - [(pyridin-2-yl) methoxy] phenyl] amino] -3-cyano-7-ethoxyquinolin-6-yl] -4- (dimethylamino) but- 2- enamide and described in PCT publication No. WO 05/028443), lapatinib or lapatinib ditosylate (sold under the trade name Tykerb® by GlaxoSmithKline). Such a combination will be useful in, for example, HER2 positive breast cancers and gastric cancers with amplified HER2. As a therapeutic target, HER3 (ErbB3 presents the challenge of being an inactive tyrosine kinase thereby preventing the utility of ATP-tyrosine kinase mimetic inhibitors (TKIs). Bypassing this challenge are antibody-mediated strategies designed to block binding to the ErbB3 ligand (for example, MM-121) or to block the dimerization of ErbB3 with ErbB2 in cells that express ErbB2 (for example, pertuzumab).
[00602] Estrogen receptor negative regulators / aromatase inhibitors: For example, Fulvestrant (sold under the trade name Faslodex®, Letrozole (sold under the trade name Femara® by Novartis) or Examestane (sold under the name commercial for Aromasin® by Pfizer.) This combination is useful in the treatment, for example, of ER positive breast cancer. The rationale for the combination is to target PI3K-related hormone resistance.
[00603] Mitogen-activated protein kinase (MEK) inhibitors: For example, XL-518 (Cas No. 1029872-29-4, available from ACC Corp.), AZD6244 or selumetinib (AstraZeneca), GSK1120212 (GlaxoSmithKline ), AZD8330 (AstraZeneca), or MEK162, Such a combination is useful in the treatment of, for example, lung cancers with mutant KRAS, colorectal (CRC) and pancreatic cancer,
[00604] Bcl2 / BclXL inhibitors: for example, ABT737 (Abbott).
[00605] Anti-androgens: For example, Nilutamide (sold under the brand name Nilandron® and Anandron®), bicalutamide (sold under the brand name Casodex®), flutamide (sold under the brand name Fulexin ™), MDV3100 (Enzalutamide, sold under the commercial name of Xtandi® by Medivation) and Abiraterona (sold under the brand name Zytiga® by Janssen). Such a combination is useful in the treatment of, for example, prostate cancer with inactivation of PTEN. The foundation for the combination aims to direct the intercommunication between the PIK3 and Androgen Receptor pathways.
[00606] Heat Shock Protein Inhibitors (HSP90): For example, Tanespimicin (17-allylamino-17-demetoxigeldanamycin, also known as KOS-953 and 17-AAG, made available by SIGMA, and described in US Patent No. 4,261 .989) and 5- (2,4-Dihydroxy-5-isopropyl-phenyl) -4- (4-morpholin-4-ylmethyl-phenyl) -isoxazol-3-carboxylic acid ethylamide (also known as AUY922 and described in PCT Publication No. W02004 / 072051). Such a combination is useful in the treatment of, for example, EGFR-dependent lung cancers or for the inhibition of EGRmut which becomes refractory to EGR inhibitors or in HER2 positive breast cancer or HER2 positive gastric cancer.
[00607] Taxane antineoplastic agents: For example, Cabazi- taxel (1-hydroxy-7β, 10β-dimethoxy-9-oxo-5β, 20-epoxitax-11 -ene- 2α, 4,13a-triyl-4-acetate- 2-benzoate-13 - [(2R, 3S) -3 - {[(tert-butoxy) carbonyl] amino} -2-hydroxy-3-phenylpropanoate), larotaxel ((2a, 3Ç, 4a, 5β, 7a, 10β , 13a) -4,10-bis (acetyloxy) -13 - ({(2R, 3S) -3 - [(tert-butoxycarbonyl) amino] -2-hydroxy-3-phenylpropanoyl} oxy) -1-hydroxy-9 -oxo- 5,20-epoxy-7,19-cyclotax-11 -en-2-yl benzoate).
[00608] Anti-mitotic agents: For example, paclitaxel (sold under the trade names Taxol and Onxal ™) and protein-bound Paclitaxel (sold under the trade name Abraxane®) and useful for the treatment of prostate cancer, vinblastine (also known as vinblastine sulfate, vincaleucoblastin and VLB, sold under the trade names Alkaban-AQ® and Velban®), vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the trade names Oncovin® and Vincasar Pfs®) and vinorelbine (sold under the trade name Navelbine®).
[00609] Anti-insulin-like growth factor 1 receptor antibodies: For example, Figitumumab (also known as CP-751.871, available from ACC Corp) and robatumumab (CAS No. 934235-44-6).
[00610] PARP (poly ADP-ribose polymerase) inhibitors: For example, BSI-201 (iniparib) and olaparib. Such a combination is useful, for example, in targeting the possible induction of DNA damage machinery by PI3K inhibitors.
[00611] Suitable therapeutic agents for adjunct therapy include steroids, anti-inflammatory agents, antihistamines, antiemetics and other agents well known to those skilled in the art for use in improving the quality of care for patients to be treated for diseases , conditions or disorders described herein,
[00612] As activation of the PI3K / Akt pathway directs cell survival, inhibiting the pathway in combination with therapies that target apoptosis in cancer cells, including radiotherapy and chemotherapy, can result in improved responses (Ghobrial et al. , CA Cancer J. Clin. 55: 178-194 (2005)). As an example, a combination of PI3 kinase inhibitor and carboplatin demonstrated synergistic effects in both in vitro proliferation and aptosis assays as well as in vivo tumor efficacy in an ovarian cancer xenograft model (Westfall and Skinner, Mol Cancer Ther. 4: 1764-1771 (2005)). Compounds of the present invention can be administered in conjunction with radiation therapy.
[00613] The compound of the present invention or pharmaceutical composition thereof can be administered by the following routes: enteral, such as nasal; rectal or oral; parenteral such as intramuscular or intravenous; or topical such as dermal administration. The compound of the present invention or its pharmaceutical composition for use in humans is preferably administered orally (for example, in the form of a tablet).
[00614] The pharmaceutical composition or combination of the present invention can be in a unit dosage of about 1 mg to about 1000 mg of active ingredient (s) for an individual from about 50 kg to about 70 kg, or about 1 mg to about 500 mg or about 1 mg to about 250 mg or about 1 mg to about 150 mg or about 0.5 mg to about 100 mg, or about 1 mg to about 50 mg of active ingredients. The unit dosage can also be from about 50 mg to about 1000 mg of active ingredients for an individual from about 50 kg to about 70 kg, or about 50 mg to about 500 mg or about 50 mg to about from 250 mg or about 50 mg to about 150 mg or about 50 mg to about 100 mg of active ingredients. The unit dosage can also be from about 100 mg to about 500 mg of active ingredient (s) for an individual from about 50 kg to about 70 kg, or about 200 mg to about 500 mg or about 300 mg to about 500 mg or about 300 mg to about 400 mg of active ingredients. These dosages can be provided as the total daily dosage and can be supplied in single or divided dosages. The dosage may depend on the particular dosage form used for the release of the active ingredients. In general, the therapeutically effective dosage of a compound, the pharmaceutical composition or combinations thereof, is dependent on the individual's species, body weight, age and individual condition, the disorder or disease or the severity of those to be treated. A doctor, pharmacist, clinician or veterinarian of common knowledge can readily determine the effective amount of each of the active ingredients needed to prevent, treat or inhibit the progression of the disorder or disease.
[00615] The properties of the aforementioned dosages are demonstrable in in vitro tests in vivo using advantageously mammals, for example, mice, rats, dogs, monkeys or isolated organs, tissues and their preparations. The compounds of the present invention can be applied in vitrona in the form of solutions, for example, aqueous solutions prepared from, for example, a concentrated solution of 10 mM DMSO, and in vivo enterally, parenterally, advantageously intravenously, for example, as a suspension or in aqueous solution. The in vitro dosage can vary between concentrations of about 10'3 molar and 10'9 molar. A therapeutically effective amount in vivo can vary depending on the route of administration between about 0.1 to about 500 mg / kg or between about 1 to about 100 mg / kg.
[00616] In general, a therapeutically effective amount of a compound of the present invention is administered to a patient in need of treatment. The term "a therapeutically effective amount" of the compound of the present invention refers to an amount of the compound of the present invention that elicits an individual's biological or medical response, for example, reduction or inhibition of an enzymatic activity or the activity of a protein or the activity of a protein complex or improve symptoms, alleviate symptoms, slow or slow the progression of the disease or prevent the disease, etc.
[00617] In another aspect, a method for treating cancer in a mammal is provided, which comprises administering to an mammal in need of such treatment, an effective amount of a compound of the present invention.
[00618] As used here, the term "individual" refers to an animal. Typically, the animal is a mammal. An individual also refers, for example, to primates (e.g., humans, men or women), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain modalities, the individual is a primate. Preferably, the individual is a human.
[00619] As used herein, the expression "inhibits", "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom or disorder or disease or a significant decrease in the baseline activity of a biological activity or process .
[00620] As used here, the expression "treat", "treating" or "treatment" of any disease or disorder, refers to (i) the improvement of the disease or disorder (ie, slowing or paralyzing or reducing development disease or at least one of its clinical symptoms); (ii) alleviate or improve at least one physical parameter including those that may not be discernible by the patient; or (iii) prevent or delay the onset or development or progression of the disease or disorder. In general, the term "treating" or "treatment" describes the handling and care of a patient for the purpose of combating the disease, condition or disorder and includes the administration of a compound of the present invention to prevent the onset of symptoms or complications , relieve symptoms or complications, or eliminate the disease, condition or disorder.
[00621] As used here, an individual is "in need" of a treatment, if that individual benefits biologically, clinically or in quality of life from such treatment (preferably, the individual is a human).
[00622] Another aspect of the invention is a product comprising a compound of the present invention and at least one other therapeutic agent (or pharmaceutical agent) as a combined preparation for simultaneous, separate or sequential use in therapy to enhance apoptosis.
[00623] In the combination therapies of the invention, the compound of the present invention and the other therapeutic agent can be manufactured and / or formulated by the same or by different manufacturers. In addition, the compound of the present invention and the other therapeutic agent (or pharmaceutical agent) can be put together in a combination therapy: (i) before the release of the combination product to doctors (for example, in the case of a kit comprising the compound of the invention and another therapeutic agent); (ii) by the doctor himself (or under the doctor's guidance) immediately before administration; (iii) in the patient himself, for example, during sequential administration of the compound of the invention and the other therapeutic agent.
[00624] Consequently, the invention provides the use of a compound of the present invention for the treatment of a disease or condition by inhibiting or antagonizing PI3K, wherein the medicament is prepared for administration with another therapeutic agent. The invention also provides for the use of another therapeutic agent in which the medicament is administered as a combination of the compound of the present invention with the other therapeutic agent.
[00625] Modalities of the present invention are illustrated by the following Examples. It should be understood, however, that the modalities of the invention are not limited to the specific details of these Examples, since other variations of these will be known or apparent in the light of the present description, for those skilled in the art. EXAMPLES
[00626] Unless otherwise specified, starting materials are generally available from commercial sources such as Aldrich Chemicals Co. (Milwaukee, Wis.), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics ( Fairlawn, NJ), Maybridge Chemical Company, Ltd. (Cornwall, England), Tyger Scientific (Prince-ton, NJ), Chem -mpex International, Inc. (Wood Dale, IL), and AstraZe-neca Pharmaceuticals (London, England ).
[00627] The abbreviations used in the Examples below have the corresponding meanings listed below. AcOH acetic acid AICh aluminum trichloride API ionization at atmospheric pressure Boc tert-butoxycarbonyl Brine saturated sodium chloride solution (in rt) br. s broad singlet nBuOH n-butanol fBu tert-butyl CDI carbonyl diimidazole Celite is a registered trademark of Celite Corp. (World Minerals Inc.), Santa Barbara, CA, USA, to assist filtration based on kieselguhr CH3CN acetonitrile conc. doublet concentrate DCE dichloroethane DCM dichloromethane DEA diethylamine DIEA N, N-diethyl-isopropylamine DMAP 4-dimethylaminopyridine DME dimethoxyethane DMF N, N-dimethylformamide DMSO dimethylsulfoxide ES-MS diethyl ether ethyl acetate Ethyl ethyl acetate Et2N EtOH ethanol H hour (s) HPLC high pressure liquid chromatography Hyflo iPr Hyflo Super Cel® isopropyl K2CO3 potassium carbonate KOH potassium hydroxide K3PO4 potassium phosphate LAH lithium hydride aluminum LC liquid chromatography Me methyl MeI methyl iodide MeOH methanol MgSO4 sulfate magnesium M multiplet min minute (s) mL milliliter (s) mp melting point MS Mass Spectrometry NaH sodium hydride NaHCO3 sodium bicarbonate Na2CO3 sodium carbonate NaHMDS sodium hexamethyldisilazane NaOH sodium hydroxide Na2SO4 sodium sulfate MgSO4 magnesium sulfate NaOAc sodium acetate NBS N-bromosuccinimide NH4Cl ammonium chloride NH4Cl ammonium chloride NH4Cl ammonia NMR nuclear magnetic resonance POCl3 phosphorus oxychloride (III) RT room temperature Rf TLC retention factor s singlet scCO2 CO2 supercritical t triplet TBAF tetrabutylammonium fluoride TBDPSCI tert-Butyldiphenylsilyl chloride TBME tert-butylmethyleter TEA triethylamine TEM , 6-tetramethylpiperidinyloxy TFA trifluoroacetic acid TF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl TMSCI trimethylsilyl chloride ÍR retention time TsCI p-toluenesulfonyl chloride TsOH p-toluenesulfonic acid UV ultraviolet General Method
[00628] 1H-NMR measurements were performed on a Bruker Ultrashield ™ 400 (400 MHz), Bruker Ultrashield ™ 600 (600 MHz) or 500 MHz DRX Bruker CryoProbe (500 MHz) spectrophotometer, whether or not using trimethylsilane as an internal standard . Chemical changes (d-values) are reported in ppm in the lower tetramethylsilane field, the coupling constants (J) are given in Hz, the pattern of spectral division is called singlet (s), doublet (c / ), double doublet (dd), triplet (f), quadruplet (q), multiplet or more superimposed signs (m), broad sign (br). Solvents are given in parentheses.
[00629] TLC were carried out on glass plates pre-coated with silica gel 60 F254 (Merck, Darmstadt, Germany) using the respective named solvents. The visualization was done in general with UV light (254 nm). HPLC conditions: LC-MS 1:
[00630] Column: Acquity HSS T3 2.1 x 50 mm, 1.8 pm. Flow: 1.2 mL / min. Column temperature: 50 ° C. Gradient: 2% to 98% B in 1.4 min, 98% B for 0.75 min, 98% to 2% B in 0.04 min, 2% B for 0.01 min; A = water + 0.05% formic acid + 3.75 mM ammonium acetate, B = acetonitrile + 0.04% formic acid.
[00631] Full tracking detection: 215 to 350 nm LC-MS 2:
[00632] Column: Acquity HSS T3 2.1 x 50 mm, 1.8 pm. Flow: 1.2 mL / min. Column temperature: 50 ° C. Gradient: 2% to 98% B in 1.4 min, 98% B for 0.75 min, 98% to 2% B in 0.04 min, 2% B for 0.01 min; A = water + 0.05% formic acid + 0.05% ammonium acetate, B = acetonitrile + 0.04% formic acid.
[00633] Full tracking detection: 215 to 350 nm LC-MS 3:
[00634] Column: Acquity HSS T3 2.1 x 50 mm, 1.8 pm. Flow: 1.0 mL / min. Column temperature: 60 ° C. Gradient: 5% to 98% B in 1.4 min, 98% B for 0.75 min, 98% to 5% B in 0.04 min, 5% B for 0.01 min; A = water + 0.05% formic acid + 3.75 mM ammonium acetate, B = acetonitrile + 0.04% formic acid.
[00635] Full tracking detection: 215 to 350 nm HPLC 1:
[00636] Column: Chromolith performance RP18e 4.6 x 100 mm, Flow: 2.0 mL / min. Gradient: 2% to 100% B in 4.5 min, 100% B for 1 min, A = water + 0.1% TFA, B = acetonitrile + 0.1% TFA
[00637] Detection: 215 nm UPLC 1:
[00638] Column: Acquity UPLC HSS T3 C18, 1.7pm 2.1 x 50 mm. Flow: 1.0 mL / min. Gradient: 5% to 100% B in 1.5 min, 100% B for 1 min; A = water + 0.1% TFA, B = acetonitrile + 0.1% TFA, Detection: 218 nm Intermediate A: 4- (4,6-dichloro-pyrimidin-2-yl) -morpholine
[00639] Intermediate A is either commercially available or can be prepared using the following procedure.

[00640] To a solution of 2,4,6-trichloropyrimidine (5.0 ml_, 42.6 mmols) in mesitylene (80 ml_) at 165 ° C was added by dropping a solution of morpholino (4.83 ml_, 55 , 4 mmols) in mesitylene (20 ml) and the suspension was stirred at 165 ° C for 30 min. The reaction mixture was treated with H2O, EtOAc and NaHCOs. The organic layer was washed with H2O and brine, dried (toSCU), filtered and concentrated. The residue was purified by flash chromatography (hexane / EtOAc, 100: 0 -> 7: 3). The residue was triturated in hexane and filtered to provide the title compound (3.36 g, 33%). tR: 1.11 min (LC-MS 1); ESI-MS: 234.2 [M + H] + (LC-MS 1). Intermediate B: 5- (4,4,5,5-Tetramethyl- [11312] dioxaborolan-2-yl) -4-trifluormethyl-pyrimidin-2-ylamine

[00641] To a suspension of the product from step B.1 (16.2 g, 66.3 mmols), bis-pinacolatodiboro (18.5 g, 72.9 mmols) and KOAc (19.5 g, 199 mmols) in dioxane (300 mL) under argon, an adduct of PdCl2 (dppf) CH2Cl2 (2.4 g, 2.98 mmol) was added and the mixture was stirred at 115 ° C for 4 h. The reaction mixture was cooled to 50 ° C and treated with EtOAc. The resulting suspension was filtered over Hyflo and washed with EtOAc. The combined filtrate was concentrated. The residue was suspended in 2 N NaOH, stirred at RT for 5 min and then Et2θ and H2O were added and the binary mixture was filtered through Hyflo. The filtrate phases were separated. The pH of the resulting aqueous layer was adjusted to 5-6 with 4N HCI and then extracted with EtOAc. The organic layer was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated in E2 O and hexane, filtered to provide the title compound (8.33 g, 42%). IR: 1.00 min (LC-MS 1); ESI-MS: 290.3 [M + H] + (LC-MS 1). Step B1: 5-Bromo-4-trifluormethyl-pyrimidin-2-ylamine

[00642] To a solution of 2-amino-4-trifluoromethylpyrimidine (25 g, 0.15 mol) in CH3CN (800 ml) was added by dripping (for 2.5 hours) NBS (34.8 g, 0.195 moles) dissolved in 200 mL of CH3CN in the dark. The mixture was stirred 4.5 h at RT in the dark and then the solvent was evaporated. The residue was dissolved in EtOAc and H2O and the binary mixture was transferred to a separate funnel. The aqueous layer was separated and extracted with EtOAc. The organic layer was washed with H2O and brine, dried with Na2SO4, filtered and evaporated. The residue was purified by chromatography on silica gel using a gradient of hexane / EtOAc 9: 1 to 3: 2. The combined pure fractions were evaporated and the residue suspended in 40mL of hexane, stirred for 10min., Filtered and washed with 2x 20mL of hexane to give the title product as a beige solid (31.2 g, 85%). IR: 0.82 min (LC-MS 1). Example 1j (S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-methyl-oxazolidin-2-one

[00643] A product solution from step 1.1 (350 mg, 1.16 mmols), Intermediate B (449 mg, 1.51 mmols), Na2COs (2M, 1.7 mL, 3.48 mmols) and PdCI2 (dppf ) -CH2 Cl2 (95 mg, 0.17 mmol) in DME (10 mL) under argon was stirred at 80 ° C for 1 h. The mixture was diluted in EtOAc and extracted with saturated NaHCO3. The organic layer was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (CH2 Cl2 / EtOH, 99.5: 0.5 98: 2). The residue was triturated in hexane, filtered and dried. The residue was purified by preparative HPLC (Waters Sun Fire C18, 30 x 100mm, 5 µm; 0.1% TFA-water / acetonitrile; 5-100% acetonitrile gradient in 20 min) to provide the title compound (260 mg , 52%). IR: 0.93 min (LC-MS 1); ESI-MS: 426.3 [M + H] + (LC-MS 1). Step 1.1: (S) -3- (6-Chloro-2-morpholin-4-yl-pyrimidin-4-yl) -4-methyl-oxazolidin-2-one

[00644] To a solution of (S) -4-methyl-2-oxazolidinone (432 mg, 4.19 mmol) in DMF (10 mL) was slowly added NaH (60% in mineral oil, 201 mg, 5.02 mmols) under an argon atmosphere and the suspension was stirred at rt for 30 min. The reaction mixture was cooled to 0 ° C and Intermediate A (1 g, 4.19 mmol) was added. The mixture was stirred at RT for 4 h. The reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (hexane / EtOAc, 97: 3 -> • 1: 1) to provide the title compound (605 mg, 47%). tR: 1.00 min (LC-MS 1); ESI-MS: 299.2 / 301.2 [M + H] + (LC-MS 1). Example 2: (S) -3- (2, -Amino-2-morpholin-4-yl-4, -trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-hydroxymethyl-515-dimethyl-oxazolidin -2-one

[00645] A solution of the product from step 2.1 (28 mg, 0.04 mmols) and TBAF (2 ml, 2.0 mmols, 1M in THF) was stirred at rt for one night. The reaction mixture was concentrated and the residue was purified by flash chromatography (DCM / MeOH, 100: 0 —► 95: 5) to give the title product. tR: 0.89 min (LC-MS 1); ESI-MS: 470.2 [M + H] + (LC-MS 1). Step 2.1: (S) -3- (2, -Amino-2-morpholin-4-yl-4, -trifluormethyl- [415 '] bipyrimidinyl-6-yl') - 4- (tert-butyl-diphenyl-silanyloxymethyl) ) -5,5-dimethyl-oxazolidin-2-one

[00646] The title compound was prepared in analogy to the procedure used for Example 1, but using the product from step 2.2. The mixing was carried out at 100 ° C for 40 min. After extraction, the residue was purified by flash chromatography (heptane / EtOAc, 100: 0 -> 30:70) to give the title product. tR: 1.45 min (LC-MS 1); ESI-MS: 708.4 [M + H] + (LC-MS 1). Step 2.2: (S) -4- (tert-Butyl-diphenyl-silanyloxymethyl) -3- (6-chloro-2-morpholin-4-yl-pyrimidin-4-yl) -5,5-dimethyl-oxazolidin-2 -one

[00647] A solution of the product from step 2.3 (95 mg, 0.25 mmols), Intermediate A (58 mg, 0.25 mmols), xantphos (10 mg, 0.02 mmols), Pd2dba3 (4.5 mg, 4.95 umol) and Cs2CO3 (121 mg, 0.37 mmoles) in dioxane under argon was stirred at 100 ° C for 3 h. The mixture was cooled to rt, diluted with EtOAc and extracted with a saturated NaHCO3 solution. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (heptane / EtOAc, 100: 0 -> 0: 100) to give the title product (85 mg, 56%). tR: 1.54 min (LC-MS 1); ESI-MS: 581.4 / 583.3 [M + H] + (LC-MS 1). Step 2.3: (S) -4- (tert-Butyl-diphenyl-silanyloxymethyl) -5,5-dimethyl-oxazolidin-2-one

[00648] The title compound was prepared in analogy to the procedure used for the procedure used for step 6.2, but using the product from step 2.4, and using Et3N instead of imidazole. The mixture was stirred at RT for 16 h. The reaction mixture was concentrated and purified by flash chromatography (heptane / EtOAc, 100: 0 -> 55:45) to give the title product. tR: 1.33 min (LC-MS 1); ESI-MS: 384.3 [M + H] + (LC-MS 1). Step 2.4: (S) -4-Hydroxymethyl-5,5-dimethyl-oxazolidin-2-one

[00649] A solution of the product from step 2.5 (110 mg, 0.59 mmols) and HCI (4M in dioxane, 5 ml, 20 mmols) was stirred at RT for 4 h. The reaction mixture was concentrated and the residue was used without further purification. Step 2.5: (S) -1,1,5,5-Tetramethyl-dihydro-oxazolo [3,4-c] oxazol-3-one

[00650] To a solution of the product from step 2.6 (190 mg, 0.73 mmols) in DMF (6 ml) under argon at 0 ° C, NaH (88 mg, 2.20 mmols, 60% in oil) was added and the The mixture was stirred at 0 ° C for 6 h. The reaction mixture was stopped with H2O and concentrated. The residue was triturated in EtOAc and filtered. The filtered solution was dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography (heptane / EtOAc, 100: 0 60:40). Step 2.6: (S) -4- (1-Hydroxy-1-methyl-ethyl) -2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester

[00651] To a solution of (S) -3-tert-butyl 4-methyl 2,2-dimethyloxazolidine-3,4-dicarboxylate (500 mg, 1.93 mmol) in THF (15 mL) under argon at 0 ° C was added by dropping methyl magnesium bromide (1.4 mL, 4.24 mmol) and the mixture was stirred at 0 ° C for 2 h. The reaction was stopped with a saturated NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried (N32SO4), filtered and concentrated. The residue was purified by flash chromatography (heptane / EtOAc, 100: 0 65:35). tR: 1.01 min (LC-MS 1); ESI-MS: 260.3 [M + H] + (LC-MS 1). Example 3: Racemically 3- (2, -amino-2-morpholino-4 '- (trifluoromethyl) -4,5, -bipyrimidin-6-yl) -4- (hydroxymethyl) -4-methyloxazolidin-2-one

[00652] A solution of intermediate B (68 mg, 0.21 mmols), the product of step 3.1 (120 mg, 0.21 mmols), a 2M solution of Na2COs (317 uL, 0.63 mmols) and tetracis ( 15 mg, 0.01 mmols) in DME (2 ml) was stirred at 80 ° C for 3 h. The reaction mixture was diluted in EtOAc and Na2SO4 was added. The resulting suspension was filtered and the filtrate was concentrated. The residue was dissolved with THF (2 ML) and TBAF (212 µL, 0.21 mmols) was added. The mixture was stirred at rt for 16 h and was concentrated. The crude product was purified by flash chromatography (DCM / EtOH, 99: 1 96: 4). The residue was triturated in DCM / hexane to provide the title compound. tR: 0.85 min (LC-MS 1); ESI-MS: 456.3 [M + H] + (LC-MS 1). Step 3.1: 4- (tert-Butyl-diphenyl-silanyloxymethyl) -3- (6-chloro-2-morpholin-4-yl-pyrimidin-4-yl) -4-methyl-oxazolidin-2-one

[00653] The title compound was prepared in analogy to the procedure described for step 2.2, but using the product from step 3.2. After extraction, the residue was purified by flash chromatography (hexane / EtOAc: 9: 1 -> 1: 1) to give the title compound. Step 3.2: 4- (tert-Butyl-diphenyl-silanyloxymethyl) -4-methyl-oxazolidin-2-one

[00654] The title compound was prepared in analogy to the procedure described for step 6.4, but using 4- (hydroxymethyl) -4-methyloxazolidin-2-one and using DCM instead of DMF. The reaction mixture was extracted with Et2θ. The organic layer was washed with H2O and brine, dried (Na2SC> 4), filtered and concentrated. The resulting solid was triturated in hexane and filtered to provide the title compound. IR: 1.20 min (LC-MS 1); ESI-MS: 339.2 / 341.2 [M + H] + (LC-MS 1). Example 3A: Initially eluting the enantiomer of 3- (2'-amino-2-morpholino-4 '- (trifluormethyl) -4,5'-bipyrimidin-6-yl) -4- (hydroxymethyl) -4-methyloxazolidin-2 -one
[00655] Absolute stereochemistry not determined.

[00656] The title compound was obtained after the chiral preparative separation of the racemic product of Example 3. (Column: Chiralpak AD-H, 30 x 250 mm. Flow 80 mL / min. ScCO2 / MeOH 85:15). IR: 3.97 min (Column: Chiralpak AD-H, 4.6 x 250 mm. Flow 3 mL / min. ScCO2 / MeOH 85:15). Example 3B: eluting the second enantiomer of 3- (2, -amino-2-morpholino-4, - (trifluormethyl) -4,5, -bipyrimidin-6-yl) -4- (hydroxymethyl) -4-methyloxazolidin-2 - ona
[00657] Absolute stereochemistry not determined.

[00658] The title compound was obtained after the chiral preparative separation of the racemic product of Example 3. (Column: Chiralpak AD-H, 30 x 250 mm. Flow 80 ml / min. ScCO2 / MeOH 85:15). IR: 4.49 min (Column: Chiralpak AD-H, 4.6 x 250 mm. Flow 3 mL / min. ScCO2 / MeOH 85:15). Example 4: (3aS, 7aS) -3- (2, -Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -hexa-hydro-benzoxazole-2 -one

[00659] A solution of the product from step 4.1 (60 mg, 0.17 mmols), intermediate B (54 mg, 0.17 mmols), Na2CO3 (2M, 260 pL, 0.52 mmols) and palladium tetracis (10 mg , 8.7 pmol) in DME (1.5 ml) under argon was stirred at 80 ° C for 2 h in a sealed flask. The reaction mixture was concentrated. The residue was purified by flash chromatography (CHhCh / EtOH, 99.8: 0.2 97.5: 2.5). The residue was dissolved in DCM (2 ml) and then treated in hexane (4 ml). The crystals were filtered and washed with hexane (3mL) to give the title compound (36 mg, 44%). tR: 1.10 min (LC-MS 1); ESI-MS: 466.3 [M + H] + (LC-MS 1). Step 4.1: (3aS, 7aS) -3- (6-Chloro-2-morpholin-4-yl-pyrimidin-4-yl) -hexa-hydro-benzoxazol-2-one

[00660] The title compound was prepared in analogy to the procedure described for step 2.2, but using the product from step 4.2. The reaction was carried out at 100 ° C for 1 h. The reaction mixture was filtered through Hyflo and concentrated. The residue was purified by flash chromatography (hexane / EtOAc: 9: 1 1: 1) to give the title compound. tR: 1.20 min (LC-MS 1); ESI-MS: 339.2 / 341.2 [M + H] + (LC-MS 1). Step 4.2: (3aS, 7aS) -Hexa-hydro-benzoxazol-2-one

[00661] (1S, 2S) -2-Aminocyclohexanol (750 mg, 6.51 mmol) and 2-Nitrophenyl chloroformate (1378 mg, 6.84 mmol) were stirred in DCE (15 mL) with DIEA (2 , 39 mL, 13.68 mmols) in a flask sealed at 90 ° C for 1 h. The reaction mixture was placed in a separatory funnel with 50mL EtOAc and 50mL of saturated NaHCOs solution. The aqueous layer was washed with 50mL of EtOAc. The organic layers were combined and washed with 50mL of H2O, 50mL of brine, dried with Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (hexane / EtOAc: 7: 3 -> 3: 7) to give the title compound (770 mg, 5.13 mmol). tR: 0.69 min (LC-MS 1); 1H NMR (400 MHz, <dmso>) δ ppm 1.19 - 1.44 (m, 3 H) 1.45 - 1.61 (m, 1 H) 1.65 (d, J = 9.77 Hz , 1 H) 1.76 (d, J = 11.34 Hz, 1 H) 1.82 - 1.93 (m, 1 H) 1.93 - 2.10 (m, 1 H) 3.03 - 3.23 (m, 1 H) 3.74 (td, J = 11.34, 3.52 Hz, 1 H) 7.53 (br. S „1 H) Example 5: (S) -3- ( 2'-Amino-2-morfolin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-methoxymethyl-oxazolidin-2-one

[00662] In a microwave vial, to a solution of the product from step 5.1 (116 mg, 0.28 mmols) and intermediate B (90 mg, 0.31 mmols) in DME (2.1 ml) were added saturated NaHCO3 solution (0.7 mL) and PdCl2 (dppf) 2.CH2 Cl2 (23 mg, 0.03 mmol). The mixture was bubbled with argon for 5 min. It was stirred at 120 ° C for 15 min under microwave irradiation. The reaction mixture was recovered in DCM and water. The layers were separated and the aqueous layer was extracted two more times with a little DCM. Then, the organic layers were combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography (DCM / MeOH: 100% - »95% DCM). The obtained residue was purified by reversed-phase flash chromatography (MeCN / H2O: 10% 100% MeCN) to give the title compound (19 mg, 13%). IR: 0.91 min (LC-MS 1); ESI-MS: 456.1 [M + H] + (LC-MS 1). Step 5.1: (S) -3- (6-Chloro-2-morpholin-4-yl-pyrimidin-4-yl) -4-methoxymethyl-oxazolidin-2-one

[00663] The title compound was prepared in analogy to the procedure described for step 2.2, but using the product from step 5.2. The reaction was carried out at 115 ° C for 80 min. The reaction mixture was concentrated and recovered with DCM / water. The layers were separated and the aqueous was extracted three times with DCM. The organic layers were combined and dried over sodium sulfate. The residue was purified by flash chromatography (heptane / EtOAc: 100% 60% heptaNo.) To give the title compound (116 mg, 22%). IR: 0.98 min (LC-MS 1); ESI-MS: 329.2 [M + H] + (LC-MS 1). Step 5.2: (S) -4-Methoxymethyl-oxazolidin-2-one

[00664] TsOH (800 mg, 4.21 mmol) was added to a solution of the product from step 5.3 (1.013 g, 4.13 mmol) in MeOH (10 mL). The mixture was stirred at rt for 90 min. Then, TsOH (140 mg, 0.74 mmols) was added and it was stirred for 70 min at RT. Then, the solvent was removed and the residue was dissolved in DCM (6 ml) with Triethylamine (1.44 ml, 10.32 mmol). A solution of triphosgene (0.613 g, 2.07 mmols) in DCM (4 mL) was slowly added to the mixture. The reaction mixture was stirred at rt for 2 h 30. The reaction was stopped with a few drops of water. It was then acidified to pH = 4 with the buffer that was added and then the layers were separated. The aqueous layer was extracted again with a little DCM. Organic layers were combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography (DCM / MeOH: 100% 90% DCM) to give the title compound (231 mg, 38%). ESI-MS: 132.1 [M + H] + (LC-MS 1). Step 5.3: (S) -4-methoxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester

[00665] NaH (265 mg, 6.63 mmols) was added to a yellow solution of (S) -1-Boc-2,2-dimethyl-4-hydroxymethyloxazolidine (AstaTech Inc., Bristol, Pennsilvania) (1 g, 4.19 mmols) in THF (10 mL). Then, the mixture was stirred for 15 minutes at room temperature, methyl sludge (323 pL, 5.19 mmols) was added to the yellow suspension and the mixture was stirred for 2 h 30 in rt. Then, water was added to stop the reaction. The solvent was removed. The residue was purified by flash chromatography (DCM / MeOH: 5% -> 10% MeOH) to give the title compound (1.013 g, 94%). ESI-MS: 246.1 [M + H] + (LC-MS 1); 1H NMR (400 MHz, <cdcl3>) δ ppm 1.48 (s, 9 H) 1.53 (br. S, 6 H) 3.30 (m, 1 H) 3.36 (s, 3 H ) 3.41 - 3.63 (m, 2 H) 3.88 - 4.00 (m, 2 H) Example 6: (4S, 5S) -3- (2, -Amino-2-morpholin-4- il-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-hydroxymethyl-5-methyl-oxazolidin-2-one

[00666] A solution of the product from step 6.1 (600 mg, 0.82 mmols) in THF (5 ml) was treated with HF.pyridine in THF (7.14 ml, 57.5 mmols) for 4 days in RT at a plastic bottle. Then, the reaction mixture was added dropwise to a mixture of saturated solution of NaHCOs (300mL) and EtOAc (200mL). Then, solid NaHCOs were added to pH ~ 8 and the layers were separated. The aqueous layer was washed with 100mL of EtOAc. The organic extracts were combined and washed with water and brine. They were then dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography (DCM / EtOH: 99: 1 95: 5). The fractions were combined and concentrated. The residue was sonicated in DCM and then hexane was added. The obtained crystals were filtered and re-purified 3 times by flash chromatography (DCM / EtAOc: 9: 1 3: 7, then Hexane / THF: 9: 1 —► 1: 1, then Hexane / THF: 7: 3 —► 1: 1) to give the title compound (243 mg, 64%). IR: 0.80 min (LC-MS 1); ESI-MS: 456.6 [M + H] + (LC-MS 1). Step 6.1: (4S, 5S) -3- (2'-Amino-2-morpholin-4-yl-4, -trifluormethyl- ^ .δ'lbipyrimidinyl-δ-ylM-fterc-butyl-diphenyl-silanyloxymetiD-δ- methyl-oxazolidin-2-one

[00667] The title compound was prepared in analogy to the procedure described for Example 1, but using the product from step 6.2. The reaction was carried out at 80 ° C for 1 h. After extraction, the residue was purified by flash chromatography (DCM / EtOH: 95.5: 0.5 97: 3) to give the title compound. IR: 1.43 min (LC-MS 1); ESI-MS: 694.5 [M + H] + (LC-MS 1). Step 6.2: (4S, 5S) -4- (tert-Butyl-diphenyl-silanyloxymethyl) -3- (6-chloro-2-morpholin-4-yl-pyrimidin-4-yl) -5-methyl-oxazolidin-2 -one

[00668] The title compound was prepared in analogy to the procedure described for step 2.2, but using the product from step 6.3. The reaction was carried out at 100 ° C for 3 h 30. The reaction mixture was removed with EtOAc and washed with saturated NaHCOa solution and brine. The organic layer was dried over sodium sulfate. The residue was purified by flash chromatography (heptane / EtOAc: 100% -> 30% heptane.) To give the title compound (116 mg, 22%). IR: 1.51 min (LC-MS 1); ESI-MS: 567.4 / 569.5 [M + H] + (LC-MS 1). Step 6.3: (4S, 5S) -4- (tert-Butyl-diphenyl-silanyloxymethyl) -5-methyl-oxazolidin-2-one

[00669] The product from step 6.4 (3.2 g, 9.31 mmols) was dissolved in DCM (32 ml) and treated with Et3N (3.25 ml, 23.29 mmols). The solution was washed with Argon and stirred for 5 min at RT. Then it was treated with triphosgene (1.382 g, 4.66 mmols) and stirred at RT for 16 h. The reaction was stopped with a saturated solution of NH4 Cl (10 mL) and stirred 10 min at RT. The water layer was separated and the organic layer washed with water. The combined aqueous layers were extracted 3x with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (heptane / EtOAc: 100% 50% liver) to give the title compound (2.22 g, 61%). IR: 1.28 min (LC-MS 1); ESI-MS: 387.3 [M + 18] + (LC-MS 1). Step 6.4: (2S, 3S) -3-Amino-4- (tert-butyl-diphenyl-silanyloxy) -butan-2-ol

[00670] D-threoninol (2 g, 19.02 mmols) was dissolved in DMF (15 ml), treated with imidazole (3.89 g, 57.1 mmols) and stirred at RT for 5 min. Then TBDPS-CI (5.13 mL, 19.97 mmols) was added to the reaction solution under argon. The reaction solution was stirred for 16 h at RT. Then, it was diluted in EtOAc and washed twice with a saturated solution of NaHCOs and once with brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (heptane / EtOAc: 100% -> 0% heptane) to give the title compound (3.21 g, 47%). tR: 0.98 min (LC-MS 1); ESI-MS: 344.3 [M + H] + (LC-MS 1). Example 7 (S) -3- (2'-Amino-2-morpholin-4-yl-4, -trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-hydroxymethyl-oxazolidin-2-one

[00671] A solution of the product from step 7.1 (200 mg, 0.35 mmols), intermediate B (131 mg, 0.39 mmols), Na2COs (2M, 526 pL, 1.05 mmols) and palladium tetracis (24 mg , 0.21 mmols) in DME (4 mL) under argon was stirred at 80 ° C for 2 h. The reaction mixture was treated with Na2SÜ4, diluted in EtOAc and the insoluble parts were filtered. The filter cake was washed three times with EtOAc and the filtrate was evaporated. Then the residue was dissolved in THF and a solution of TBAF (1N, 351 pL, 0.35 mmol) was added. The mixture was stirred for 1 h at RT. The solvent was removed and the residue was purified by flash chromatography (DCM / EtOH: 99: 1 95: 5) to give the title compound. IR: 0.74 min (LC-MS 1). Step 7.1: (R) -4- (tert-Butyl-diphenyl-silanyloxymethyl) -3- (6-chloro-2-morpholin-4-yl-pyrimidin-4-yl) -oxazolidin-2-one

[00672] The title compound was prepared in analogy to the procedure described for step 2.2, but using the product from step 7.2. The reaction was carried out at 100 ° C for 3 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by flash chromatography (hexane / EtOAc: 9: 1 —► 6: 4) to give the title compound. IR: 1.53 min (LC-MS 1); ESI-MS: 553.4 / 555.5 [M + H] + (LC-MS 1). Step 7.2: (R) -4- (tert-Butyl-diphenyl-silanyloxymethyl) -oxazolidin-2-one

[00673] The title compound was prepared in analogy to the procedure described for step 6.4, but using (S) -4- (hydroxymethyl) oxazolidin-2-one (SpeedChemical Corp. Shanghai), and DCM instead of DMF . The reaction was performed at RT for 16 h. The reaction mixture was diluted with water and extracted twice with Et2θ. The organic layers were combined, washed with water and brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (hexane / EtOAc: 98: 2 4: 6). The residue was treated with hexane and Et2θ. The obtained crystals were filtered to give the title compound. IR: 1.26 min (LC-MS 1), 1H NMR (400 MHz, <dmso>) δ ppm 0.98 (s, 9 H) 3.51 - 3.63 (m, 2 H) 3.88 (dd, J = 8.60, 4.30 Hz, 1 H) 4.14 (dd, J = 8.60, 4.69 Hz, 1 H) 4.30 - 4.38 (m, 1 H) 7.37 - 7.50 (m, 6 H) 7.57 - 7.65 (m, 4 H) 7.71 (s, 1 H). Example 8: (4S, 5R) -3- (2'-Amino-2- (D8-morpholin-4-yl) -4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-hydroxymethyl -5-methyl-oxazolidin-2-one

[00674] The title compound was prepared in analogy to the complete sequence described for Example 6, but using the product from step 8.1 instead of intermediate A and D-alo-Treoninol instead of D-threoninol. tR: 0.79 min (LC-MS 1); ESI-MS: 464.5 [M + H] + (LC-MS 1). Step 8.1: 4- (4,6-Dichloro-pyrimidin-2-yl) -D8-morpholino

[00675] 2,4,6-trichloropyrimidine was dissolved in EtOH with EtsN and D8-morpholino. The reaction mixture was stirred at rt for 1 h. It was diluted with saturated NaHCOs and extracted twice with EtOAc. The organic extracts were combined and washed with moorish salt. Then it was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (hexane / EtOAc: 0% hexane 40%). tR: 0.94 min (LC-MS 1); ESI-MS: 242.3 / 244.2 [M + H] + (LC-MS 1). Example 9; (S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4- (2-hydroxy-ethyl) -oxazolidin-2-one

[00676] The title compound was prepared in analogy to the procedure described for Example 6 but using the product from step 9.1. The extraction was carried out in DCM. The residue was purified by preparative HPLC (H2O / ACN) then by flash chromatography (DCM / MeOH, 100: 0 95: 5). tR: 0.78 min (LC-MS 1); ESI-MS: 456.2 [M + H] + (LC-MS 1). Step 9.1: (S) -3- (2, -Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4- (tert-butyl-diphenyl- silanyloxymethyl) - [1,3] oxazinan-2-one

[00677] The title compound was prepared in analogy to the procedure described for Example 1, but using the product from step 9.2. The reaction was carried out at 120 ° C for 15 min. The reaction mixture was dissolved in DCM and extracted with H2O. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (heptane / EtOAc, 8: 2 -> 4: 6). tR: 1.54 min (LC-MS 1); ESI-MS: 694.3 [M + H] + (LC-MS 1). Step 9.2: (S) -4- (tert-Butyl-diphenyl-silanyloxymethyl) -3- (6-chloro-2-morpholin-4-yl-pyrimidin-4-yl) - [1,3] oxazinan-2- ona

[00678] The title compound was prepared in analogy to the procedure described for step 2.2, but using the product from step 9.3. The reaction was carried out at 115 ° C for 2.5 h. The mixture was concentrated. The residue was purified by preparative HPLC (H2O / ACN), then by flash chromatography (heptane / EtOAc, 9: 1 -> 0: 100). IR: 1.49 min (LC-MS 1); ESI-MS: 567.3 [M + H] + (LC-MS 1). Step 9.3: (S) -4- (tert-Butyl-diphenyl-silanyloxymethyl) - [1,3] oxazinan-2-one

[00679] To a solution of the product from step 9.4 (900 mg, 2.03 mmols) in THF (40 ml) under argon was added 60% NaH in oil (160 mg, 4.0 mmols) and the mixture was stirred in rt for 4h. The mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (heptane / EtOAc, 100: 0 -> 0: 100). IR: 1.23 min (LC-MS 1); ESI-MS: 370.2 [M + H] + (LC-MS 1). Step 9.4: [(S) -1- (tert-Butyl-diphenyl-silanyloxymethyl) -3-hydroxy-propyl] -carbamic acid tert-butyl ester

[00680] To a solution of the product from step 9.5 (40 g, 73 mmols) in TBME (400 ml) at 0 ° C was added by LiBhU drip (2M in THF, 74 ml, 146 mmols) and the mixture was stirred at 0 ° C for 10 min then heated to rt and stirred for 5 h. The reaction mixture was stopped with H2O then with a 0.5 M citric acid solution. The mixture was extracted with TBME. The organic layer was dried (MgSCU), filtered and concentrated. The product was used without further purification. Step 9.5: (S) -3-tert-Butoxycarbonylamino-4- (tert-butyl-diphenyl-silanyloxy) -butyric acid benzyl ester

[00681] The title product was prepared in analogy to the procedure described for step 6.4. Rt 0.7 (hexane / EtOAc, 8: 2) Step 9.6: benzyl ester of (S) -3-tert-Butoxycarbonylamino-4-hydroxy-butyric acid

[00682] To a solution of Boc-4-benzyl ester of L-aspartic acid (100 g, 309 mmols) in DME (1.8 L) at -20 ° C was added NMM (34 mL, 309 mmols) then by iso-butylchloroformate drip (40 mL, 309 mmols) and the mixture was stirred at -20 ° C for 20 min. The reaction mixture was filtered and the filtrate was cooled to -20 ° C. NaBH4 (17.5 g, 463 mmols) was added in portions at -20 ° C. The mixture was allowed to warm up and stirred at rt for 1 h. The mixture was stopped with a 20% citric acid solution and then extracted with AcOEt. The organic layer was washed with a solution of NaHCOa, H2O and brine, dried (MgSCU), filtered and concentrated. The product was used without further purification in the next step. Example 10: (4S, 5R) -3- [2'-Amino-2 - ((S) -3-methyl-morpholin-4-yl) -4'- trifluormethyl- [4,5'lbipyrimidinyl-6-yl ] -4-hydroxymethyl-5-methyl-oxazolidin-2-one

[00683] The title compound was prepared in analogy to the entire sequence described for Example 6, but using the product from step 10.1 instead of intermediate A and D-alo-Treoninol instead of D-threoninol. The mixture was added dropwise to a saturated solution of Na2CO3. After the addition, a saturated solution of NaHCOs was added (the final pH was around 7-8). It was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC (Waters Sun Fire C18, 30 x 100mm, 5 µm; 0.1% TFA-water / acetonitrile; 5-100% acetonitrile gradient in 20 min). The residue was recrystallized from Et2O / hexane (3/1). The crystals were filtered and washed with hexane to give the title compound. tR: 2.89 min (HPLC 1); ESI-MS: 470.3 [M + H] + (LC-MS 1); mp 217.7 ° C (start). Step 10.1: (S) -4- (4,6-Dichloro-pyrimidin-2-yl) -3-methyl-morpholine

[00684] 2,4,6-Trichloropyrimidine (100 mg, 0.53 mmols) was dissolved in dioxan (2 ml) with DIPEA (280 pL, 1.6 mmols) and (S) -3-methylmorpholine (54 mg , 0.53 mmols). The reaction mixture was heated to 130 ° C under microwave irradiation at 15 min. It was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by pre-parative HPLC (Waters Sun Fire C18, 30 x 100mm, 5 µm; 0.1% TFA-water / acetonitrile; 5-100% acetonitrile gradient in 20 min) to provide the title compound ( 45 mg, 34%). IR: 3.70 min (HPLC 1); ESI-MS: 248.2 / 250.2 [M + H] + (LC-MS 1). Example 11 (for comparison): 3- (2, -Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -oxazolidin-2-one

[00685] The title compound was prepared in analogy to Example 5 (including step 5.1), but using the product from step 11.1. The reaction was carried out at 100 ° C for 1 h. The extraction was carried out in EtOAc. The residue was purified by flash chromatography (heptane / EtOAc, 100: 0 0: 100). tR: 0.87 min (LC-MS 1); ESI-MS: 412.4 [M + H] + (LC-MS 1). Step 11.1: 3- (6-Chloro-2-morpholin-4-yl-pyrimidin-4-yl) -oxazolidin-2-one

[00686] The title compound was prepared in analogy to the entire sequence described for step 2.2, but using oxazolidin-2-one. tR: 0.93 min (LC-MS 1); ESI-MS: 285.5 / 287.4 [M + H] + (LC-MS 1). Example 12: (4S, 5R) -3- (2, -amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5'lbipyrimidinyl-6-yl) -5-methyl-2-oxo ester -oxazolidin-4-ylmethyl formic acid

[00687] The compound of Example 18 (47 mg, 0.10 mmol) was dissolved in formic acid (80 µL, 2.09 mmol) and stored at 5 ° C for 4 days. Then it was allowed to warm up to RT and it was stored for 2 days. Then it was recovered in EtOAc and washed with a saturated solution of NaHCOs and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Waters Sun Fire C18, 30 x 100mm, 5 µm; 0.1% TFA-water / acetonitrile; 5-70% acetonitrile gradient in 20 min) to provide the title compound (57 mg , 80%). IR: 0.88 min (LC-MS 1); ESI-MS: 484.4 [M + H] + (LC-MS 1). Example 13: (S) -3- [2'-Amino-2 - ((S) -3-methyl-morpholin-4-yl) -4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-ill- 4-methyl-oxazolidin-2-one

[00688] The title compound was prepared in analogy to the entire sequence described for Example 11, but using the product from step 10.1 instead of intermediate A and (S) -4-methyl-2-oxazolidinone instead of oxazolidin-2 -one. The residue was purified by flash chromatography (DCM / EtOH: 99.8 / 0.2 98/2) and then by preparative HPLC (Wa Sun Sun C18, 30 x 100mm, 5 µm; 0.1% TFA-water / acetonitrile; 5-100% acetonitrile gradient in 20 min) to provide the title compound (35 mg, 32%). tR: 0.98 min (LC-MS 1); ESI-MS: 440.1 [M + H] + (LC-MS 1). Example14: (S) -3- (2'-Amino-2-morpholin-4-yl-4, -trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -5-hydroxymethyl-oxazolidin-2-one

[00689] The title compound was prepared in analogy to the procedure described for Example 6, but using the product from step 14.1. The residue was purified by flash chromatography (DCM / MeOH, 100: 0 95: 5). tR: 0.77 min (LC-MS 1); ESI-MS: 442.2 [M + H] + (LC-MS 1). Step 14.1: (S) -3- (2, -Amino-2-morpholin-4-yl-4, -trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -5- (tert-butyl-diphenyl- silanyloxymethyl) -oxazolidin-2-one

[00690] The title compound was prepared in analogy to the procedure described for Example 5, but using the product from step 14.2. The reaction was carried out at 100 ° C in an oil bath for 1 h. The extraction was carried out in EtOAc. The residue was purified by flash chromatography (heptane / EtOAc, 100: 0 0: 100). tR: 1.40 min (LC-MS 1); ESI-MS: 680.3 [M + H] + (LC-MS 1). Step 14.2: (S) -5- (tert-Butyl-diphenyl-silanyloxymethyl) -3- (6-chloro-2-morpholin-4-yl-pyrimidin-4-yl) -oxazolidin-2-one

[00691] The title compound was prepared in analogy to the procedure described for step 2.2, but using the product from step 14.3. After extraction, the residue was purified by flash chromatography (heptane / EtOAc, 100: 0 - + 40:60). tR: 1.49 min (LC-MS 1); ESI-MS: 553.3 [M + H] + (LC-MS 1). Step 14.3: (S) -5- (tert-Butyl-diphenyl-silanyloxymethyl) -oxazolidin-2-one

[00692] To a solution of the product from step 14.4 (2.72 g, 8.27 mmols) and EtsN (2.88 mL, 20.67 mmols) in DCM under argon was added by triphosgene drip (982 mg, 3, 31 mmols) and the mixture was stirred at rt for 5 h. The reaction mixture was stopped with an NH4 Cl solution. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (liver / EtOAc, 100: 0 0: 100). tR: 1.21 min (LC-MS 1); ESI-MS: 373.2 [M + H] + (LC-MS 1). Step 14.4: (S) -1-Amino-3- (tert-butyl-diphenyl-silanyloxy) -propan-2-ol

[00693] The title compound was prepared in analogy to the procedure described for step 6.4, but using (S) -3-aminopropane-1,2-diol and using EtsN instead of imidazole. After extraction, the residue was purified by flash chromatography (DCM / MeOH, 100: 0 -> 90/10). tR: 0.93 min (LC-MS 1); ESI-MS: 330.2 [M + H] + (LC-MS 1). Example 15: (4S, 5R) -3- (2, -Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -5-hydroxymethyl-4-methyl -oxazolidin-2-one

[00694] The title compound was prepared in analogy to the entire sequence described for Example 6, but using the product from step 15.1 instead of D-threoninol. tR: 0.98 min (LC-MS 1); ESI-MS: 344.3 [M + H] + (LC-MS 1). Step 15.1: (2R, 3S) -3-Amino-butane-1,2-diol

[00695] The title compound was prepared in analogy to the procedure in step 19.1, but using the product from step 15.2. The residue was purified by flash chromatography (DCM / EtOH: 99.8 / 0.2 -> 98/2) and then by preparative HPLC (Waters Sun Fire C18, 30 x 100mm, 5 µm; 0.1% TFA-water / acetonitrile; 5-100% acetonitrile gradient in 20 min) to provide the title compound (35 mg, 32%). tR: 0.98 min (LC-MS 1); ESI-MS: 440.1 [M + H] + (LC-MS 1). Step 15.2: N-Benzyl-N - [(S) -1 - ((R) -2,2-dimethyl- [1,3] dioxolan-4-yl) -ethyl-hydroxylamine

[00696] The title compound is the second isomer formed during step 19.2 (1.07 g, 57%). tR: 0.91 min (LC-MS 1); ESI-MS: 252.2 [M + H] + (LC-MS 1). Example 16: (S) -3- (2, -Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5'lbipyrimidinyl-6-iD-5-methyl-oxazolidin-2-one

[00697] The title compound was prepared in analogy to Example 11, but using the product from step 16.1 instead of (R) -4-methyl-2-oxazolidinone. The reaction was carried out at 100 ° C for 1 h. The reaction mixture was recovered with EtOAc. It was washed twice with a saturated solution of NaHCOs and once with brine. The organic layer is dried over sodium sulfate. The residue was purified by flash chromatography (heptane / EtOAc: 0% -> 85% EtOAc) to give the title compound (9.6 mg, 58%). tR: 0.94 min (LC-MS 1); ESI-MS: 426.2 [M + H] + (LC-MS 1). Step 16.1: (S) -5-Methyl-oxazolidin-2-one

[00698] The title compound was prepared in analogy to the procedure described for step 6.3, but using (S) -1-aminopropan-2-ol. The reaction was carried out in RT for 3 H. The reaction was stopped with saturated NH4CI solution (10 mL) and stirred for 10 min at RT. The water layer was separated and the organic layer washed with water. The combined aqueous layer was extracted 3x with DCM. The combined organic layers were dried over filtered and concentrated IS ^SOψ. The residue was purified by flash chromatography (heptane / EtOAc: 0% 100% EtOAc) to give the title compound (38 mg, 9%). 1H NMR (400 MHz, <DMSO>) δ ppm 1.27 (d, J = 6.25 Hz, 3 H) 2.94 - 3.08 (m, 1 H) 3.48 - 3.58 (m , 1 H) 4.62 (m, 1 H) 7.37 (br. S., 1 H) Example 17: (S) -3- (2, -amino-2-D8-morpholino-4, - ( trifluormethyl) - [4,5'-bipyrimidin1-6-yl) -4-methyloxazolidin-2-one

[00699] The title compound was prepared in analogy to the procedure described for Example 4, but using the product from step 17.1. After completion, the reaction mixture was filtered through celite and concentrated. The residue was purified by flash chromatography (DCM / EtOH, 99.5: 0.5 -> 98: 2). The residue was triturated in DCM and washed with hexane to provide the title compound. IR: 0.89 min (LC-MS 1); ESI-MS: 434.4 [M + H] + (LC-MS 1); Rf: 0.67 (DCM / EtOH, 95: 5). Step 17.1: (S) -3- (6-Chloro-2-D8-morpholin-4-yl-pyrimidin-4-yl) -4-methyl-oxazolidin-2-one

[00700] The title compound was prepared in analogy to the procedure described for step 2.2, but using the product from step 8.1 and (S) -4-methyl-2-oxazolidinone. The extraction was carried out in DCM. The residue was purified by flash chromatography (heptane / EtOAc, 9: 1 7: 3). tR: 0.97 min (LC-MS 1); ESI-MS: 307.3 / 309.3 [M + H] + (LC-MS 1). Example 18: (4S, 5R) -3- (2, -Amino-2-morpholin-4-yl-4, -trifluoromethyl- [4,5'lbipyrimidinyl-6-yl) -4-hydroxymethyl-5-methyl- oxazolidin-2-one

[00701] The title compound was prepared in analogy to the entire sequence described for Example 6, but using D-allo-threoninol instead of D-threoninol. The reaction was performed at RT for 33 h. The mixture was added dropwise to a saturated solution of Na2COs. After the addition, the pH was around 7-8. It was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC (Waters Sun Fire C18, 30 x 100mm, 5 µm; 0.1% TFA-water / acetonitrile; 5-60% acetonitrile gradient in 20 min). The fractions were combined and basified with a 5% NaHCOs solution. The product precipitated and was filtered. To eliminate residual palladium, the product was dissolved in DCM / MeOH (4/1) and passed through a Polymerlabs MP-Thiol SPE cartridge and then the solvent was evaporated. Several batches were produced based on this method and several were developed to provide a crystalline material as follows. Lot A:
[00702] For the preparation of this batch, the product was not passed through a SPE MP-Thiol cartridge from Polymerlabs. The pure fractions obtained after preparative HPLC were combined and treated with NaHCOa. The CH3CN was evaporated after which the product crystallized. The product was collected by filtration, washed with and dried to give the title compound as a white solid, m.p. 221.3 ° C (start). Lot B:
[00703] For the preparation of this batch the product was not passed through a SPE MP-Thiol cartridge from Polymerlabs. The pure fractions obtained after preparative HPLC were combined and treated with solid NaHCOs. The CH3CN was evaporated after which the product crystallized. The aqueous mixture was kept for 1 h in the refrigerator, filtered, washed with water and dried under HV light overnight to provide a white solid, m = 298 mg. m.p. 249.9 ° C (start) Lot C:
[00704] For the preparation of this batch, the product was not passed through a SPE MP-Thiol cartridge from polymerlabs. The pure fractions obtained after the preparative HPLC were combined and evaporated. The residue was removed in CH3CN and then water containing 0.1% TFA was added followed by solid NaHCOs. The solution is concentrated and the precipitate is filtered, washed with water and dried to give the title product as a white solid, m.p. 237.9 ° C (start) Lot D:
[00705] After passing through the polymerlabs MP-Thiol SPE cartridge, the solvent was evaporated. The residue was dissolved in CH3CN and then diluted with the same amount of water. The CH3CN was evaporated and shortly before crystallization of the product, some crystals from Lot B were added. CH3CN was then completely evaporated and the suspension was cooled in the refrigerator. It was then filtered, collected and dried under HV overnight to provide the title product as a white solid, m.p. 259.0 ° C (start) Lot E:
[00706] Same procedure as described for 0 Lot C, a few more crystals from Lot D were added to induce crystallization. The title product was obtained as a white solid, mp 258.8 ° C (start). Example 19: (4S, 5S) -3- (2, -Amino-2-morpholin-4-yl-4'-trifluoromethyl- [4,5 '] bipyrimidinyl-6-yl) -5-hydroxymethyl-4-methyl -oxazolidin-2-one

[00707] The title compound was prepared in analogy to the entire sequence described for Example 6, but using product from step 19.1 instead of D-threoninol. The reaction was carried out at RT for 16 h 30. The mixture was added dropwise to a saturated solution of N32CO3. After the addition, it was diluted with water and extracted twice with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by preparative HPLC (Waters Sun Fire C18, 30 x 100mm, 5 µm; 0.1% TFA-water / acetonitrile; 5-80% acetonitrile gradient in 20 min) to give the title compound (16, 3 mg, 75%). IR: 2.79 min (HPLC 1); ESI-MS: 456.1 [M + H] +. Step 19.1: (2S, 3S) -3-Amino-butane-1,2-diol

[00708] The product from step 19.2 was stirred in HCI in EtOH solution for 2 h at RT. The solvent was removed to give the title compound as an HCI salt (303 mg, 100%). 1H NMR (400 MHz, <dmso>) δ ppm 1.08 (d, J = 6.65 Hz, 3 H) 3.18 - 3.33 (m, 1 H) 3.33 - 3.45 (m , 1 H) 3.61 - 3.72 (m, 1 H) 7.85 (br. S., 2 H). Step 19.2: (S) -1 - ((S) -2,2-Dimethyl- [1,3] dioxolan-4-yl) -ethylamine

[00709] The product from step 19.3 (product 2, last elution, 538 mg, 2.14 mmol) was dissolved in AcOH (25 mL) with Pd / C (100 mg) and the reaction mixture was stirred at RT for 11 h under H2 conditions. It was then filtered over Celite and then the solvent was removed to give the title compound (311 mg, 100%). 1H NMR (400 MHz, <dmso>) δ ppm 0.90 - 1.04 (m, 3 H) 1.16 - 1.38 (m, 6 H) 2.76 - 2.90 (m, 1 H ) 3.75 (dd, J = 13.86, 7.22 Hz, 2 H) 3.90 (br, s „1 H); tR: 3.13 min (HPLC 1). Step 19.3: N-Benzyl-N - [(R) -1 - ((S) -2,2-dimethyl- [1,3] dioxolan-4-yl) -ethyl-hydroxylamine and N-Benzyl-N- [ (S) -1 - ((S) -2,2-dimethyl- [1,3] dioxolan-4-yl) - ethyl-hydroxylamine

[00710] To a well stirred solution of 1.48g (6.29 mmols) of the product from step 19.4 in 80 ml of EtsO was added 6.29 ml (6.29 mmols) of 1M EtzAICI in hexanes in one portion and the stirring was continued for 15 min. The mixture was then cooled to -60 ° C and treated with 6.29 ml (18.87 mmoles) of methylmagnesium bromide in Et20. The mixture was stirred for 2 h at -60 ° C and then allowed to warm slowly to RT under stirring overnight. After that, the reaction was treated with NaOH (2M, 40mL). After stirring for 15 min at RT, the mixture was extracted 3 x 120 with E2O. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue is dissolved in MeOH and purified by prep HPLC. reverse phase injection in 8 injections (H2O [+ 0.1% TFAJ / CHaCN 97: 3 to 50:50 in 20min.):
[00711] - Fractions 1 - 3 were collected together and basified with ~ 2g of NaHCOs, before being concentrated. The resulting layer was extracted with 2 x 150mL Et2θ and the combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to give 1.01 g of a colorless oil, which slowly crystallized (-99% pure by 1HNMR; HPLC Rt = 2.36; ESI-MS: 252.2 [M + H] + (LC-MS 1)) -> Product 1
[00712] - Fractions 5 - 7 were collected together and basified with ~ 2g NaHCOs, before being concentrated. The resulting suspension was extracted with 2 x 150mL Et2θ and the combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to give 363 mg of a white solid (-99% pure by 1HNMR; HPLC Rt = 2.44; ESI- MS: 252.3 [M + H] + (LC-MS 1)) -> Product 2. Step 19.4: (S, Z) -N - ((2,2-dimethyl-1,3-dioxolan- 4-yl) methylene) -1- phenylmethanamine

[00713] 1.50 g (11.53 mmols) of (R) -2,2-Dimethyl-1,3-dioxolane-4-carboxaldehyde (Fluorochem, Hadfield, UK) were dissolved in 60mL of DCM and treated with 1 , 64 g (11.53 mmols) of sodium sulfate. The reaction mixture was washed with argon and treated with a solution of 1.42 g (11.53 mmols) of N-benzylhydroxylamine (prepared from the commercially available hydrochloride salt) in 20 ml of CH2 Cl2. The reaction mixture was stirred under argon at RT for 16.5 h and then filtered. Silica gel was added to the filtrate and pre-absorbed, before being purified by silica gel chromatography (gradient: Heptane / EtOAc 0% -100% in 30min). Fr. 20 - 80 were collected and evaporated and dried under vacuum overnight to give 1.48 g of a white solid (-100% pure by HPLC, Rt = 1.43); ESI-MS: 236.2 [M + H] + (LC-MS 1)) Example 20: (R) -3- (2, -Amino-2-morpholin-4-yl-4'-trifluoromethyl- [4 , 5'lbipyrimidinyl-6-yl) -5-hydroxymethyl-oxazolidin-2-one

[00714] The title compound was prepared in analogy to the entire sequence described for Example 6, but using (R) -3-aminopropane-1,2-diol instead of D-threoninol. The reaction was performed at RT for 16 h. Then, the reaction mixture was carefully stopped with NaHCOs. Then, it was diluted with EtOAc and washed twice with saturated NaHCOs solution and once with brine. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (DCM / EtOH: 0% -> 10% MeOH) to give the title compound (22.8 mg, 38%), tp: 0.77 min (HPLC 1); ESI-MS: 442.2 [M + H] + (LC-MS 1). Example 21: (3aR, 6aR) -3- (2, -amino-2-morpholino-4, - (trifluoromethyl) - [4,5'-bipyrimidinl-6-yl) tetrahydrofuro [3,4-d] oxazole-2 (3H) -one

[00715] A solution of (3aR, 6aR) -3- (6-chloro-2-morpholinopyrimidin-4-yl) tetrahydrofuro [3,4-d] oxazol-2 (3H) -one (100 mg, 0.306 mmols), intermediate B (115 mg, 0.398 mmols), K3PO4 (195 mg, 0.918 mmols) and PdCl2 (dppf) -CH2Cl2 (25 mg, 0.031 mmols) in DME / H2O (2.2 ml) under argon was stirred at 80 ° C for 1.5 h. The mixture was diluted in EtOAc and extracted with saturated NaHCO3. The organic layer was washed with H2O and brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (hexane-EtOAc 70:30 -> 0: 100) to provide the title compound as a colorless solid (88 mg, 62%): tR = 0.84 min (LC-MS 3) ; ESI-MS: 454 [M + H] + (LC-MS 3). Step 21.1: (3aR, 6aR) -3- (6-Chloro-2-morpholinopyrimidin-4-yl) tetrahydrofuro [3,4-d] oxazol-2 (3H) -one

[00716] To a solution of (3aR, 6aR) -tetrahydrofuro [3,4-d] oxazol-2 (3H) -one (500 mg, 3.87 mmol), 4- (4,6-dichloropyrimidin- 2-yl) morpholino (1088 mg, 4.65 mmols) and CS2CO3 (2.14 g, 6.58 mmols) in dioxane (20 mL) was added, after degassing with argon, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (157 mg, 0.271 mmols) and Pd2 (dba) 3 (70.9 mg, 0.077 mmols) and the reaction mixture was heated for 6 h at 85 ° C. The reaction mixture was added to a 10% aqueous NaHCOs solution and extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was triturated in MeOH overnight, filtered and dried to provide the title compound as a colorless solid (1.12 g, 87%): tR = 0.92 min (LC-MS 3); ESI-MS: 327, 329 [M + H] + (LC-MS 3). Step 21.2: (3aR, 6aR) -Tetrahydrofuro [3,4-dloxazol-2 (3H) -one

[00717] To a solution of (3R, 4R) -4-aminotetrahydrofuran-3-ol (1.1 g, 7.88 mmol) and DIEA (4.54 mL, 26.0 mmol) in CH2 Cl2 (30 ml) (bis (trichloromethyl) carbonate (1.75 g, 5.91 mmols) dissolved in CH2 Cl2 (5 ml) in RT was added over a period of 30 min. After stirring for 0.5 h at 25 ° C, The reaction mixture was added to an aqueous solution of K2CO3, stirred for 1 h and 0 CH2 Cl2 was evaporated The aqueous layer was washed with Et2θ and then evaporated until dry The residue was triturated with EtOH / THF 1: 1, the inorganic salts removed by filtration through a plug of silica gel and the filtrate was concentrated to provide the title compound as a beige solid (930 mg, 90%): ESI-MS: 147 [M + NH] + Example 22: (3aR *, 6R *, 6aR *) - 3- (2, -Amino-2-morpholino-4, - (trifluoromethyl) - [4,5'-bipyrimidinl-6-yl) -6-hydroxyhexa-hydro-2H-cyclopenta [d] oxazol-2-one

[00718] To a solution of (3aR *, 6R *, 6aR *) - 3- (2'-amino-2-morpholino-4 '- (trifluoromethyl) - [4,5'-bipyrimidin] -6-yl) -6 - ((tert-butyldimethylsilyl) oxy) hexahydro-2H-cyclopenta [d] oxazol-2-one (810 mg, 1.253 mmols) in THF (12 mL), was added by dripping TBAF 1M in THF (1 , 0 mL, 1.0 mmols) at 0 ° C. The reaction mixture was stirred for 30 min at 0 ° C and 2 h in RT before evaporation. The residue was purified by flash chromatography (hexane-THF 60:40 0: 100). The residue was triturated in Et2O, filtered and dried. The residue was purified by preparative HPLC (Waters Sun Fire C18, 30 x 100mm, 5 µm; 0.1% TFA-water / acetonitrile; 5-100% acetonitrile gradient in 20 min) to provide the title compound (430 mg , 72%); tR = 0.93 min (UPLC 1), tR = 0.81 min (LC-MS 3); ESI-MS: 468 [M + H] + (LC-MS 3). Step 22.1: (3aR *, 6R * .6aR *) - 3- (2'-Amino-2-morpholino-4, - (trifluoromethyl) - [4,5'-bipyrimidinl-6-yl) -6 - (( tert-butyldimethylsilyl) oxy) hexahydro-2l-1-cyclopenta [dloxazol-2-one

[00719] The title compound was prepared in analogy to the procedure described for Example 21 from (3aR *, 6R *, 6aR *) - 6- ((tert-butyldimethylsilyl) oxy) -3- (6- chloro-2-morpholinopyrimidin-4-yl) hexahydro-2H-cyclopenta [d] oxazol-2-one and intermediate B and using Pd (PFs) 4 instead of PdCl2 (dppf) -CH2Cl2 and Na2COs instead of K3PO4 to provide the title compound after crystallization from EtOAc / hexane as a white solid: ÍR = 1.62 min (UPLC 1), ÍR = 1.47 min (LC-MS 3); ESI-MS: 582 [M + H] + (LC-MS 3). Step 22.2: (3aR * .6R *, 6aR *) - 6 - ((tert-butyldimethylsilyl) oxy) -3- (6-chloro-2-morpholinopyrimidin-4-yl) hexahydro-2H-cyclopenta [d] oxazol-2-one

[00720] The title compound was prepared in analogy to the procedure described for step 21.1 from (3aR *, 6R *, 6aR *) - 6 - ((tert-butyldimethylsilyl) oxy) hexahydro-2H- cyclopenta [d] oxazol-2-one and intermediate daily A: tR = 1.76 min (UPLC 1), tR = 1.58 min (LC-MS 3); ESI-MS: 455, 457 [M + H] + (LC-MS 3). Step 22.3: (3aR *, 6R * 16aR *) - 6 - ((tert-Butyldimethylsilyl) oxy) hexahydro-2H-cyclopenta [d] oxazol-2-one

[00721] To a suspension of (3aR *, 6R *, 6aR *) - 6 - ((tert-butyldimethylsilyl) oxy) -3 - ((2-nitrophenyl) sulfonyl) hexahydro-2H-cyclopenta [d] oxazole -2-one (1.47 g, 3.32 mmols) and CS2CO3 (2.164 g, 6.64 mmols) in DMF (25 ml) N-acetyl-L-cysteine (0.921 g, 5.65 mmols) was added and the reaction mixture was stirred for 16 h at RT. The reaction mixture was evaporated and the residue suspended in a saturated solution of NaHCO3 and extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated. The title compound was obtained after purification by flash chromatography (heptane / EtOAc 90:10 50:50) as a yellow oil (0.84 g, 98%): TLC (heptane / EtOAc 1: 1) Rf = 0, 28. Step 22.4: (3aR *, 6R *, 6aR *) - 6 - ((tert-Butyldimethylsilyl) oxy) -3 - ((2-nitrophenyl) sulfonyl) hexahydro-2H-cyclopenta [d] oxazol-2-one

[00722] To a solution of (3aR *, 6R *, 6aR *) - 6-hydroxy-3 - ((2-nitrophenyl) sulfonyl) hexahydro-2H-cyclopenta [d] oxazol-2-one (1, 2 g, 3.66 mmols) and 2,6-lutidine (0.851 ml, 7.31 mmols) in CH2 Cl2 (25 ml) were added by dripping at 0 ° C tert-butyldimethylsilyl trifluoromethanesulfonate (1.091 ml, 4.75 mmols). The reaction mixture was stirred for 1 h at 0 ° C followed by 2 h in RT. The reaction mixture was diluted with CH2 Cl2 and washed with aqueous solution of NaH2PO4 20% and H2O, dried over MgSO4, filtered and concentrated. The title compound was obtained after crystallization from EtOAc / heptane as a white solid (1.5 g, 88%): TLC (heptane / EtOAc 1: 1) Rf = 0.54; tR = 1.58 min (UPLC 1), tR = 1.43 min (LC-MS 3); ESI-MS: 460 [M + NH4] + (LC-MS 3). Step 22.5: (3aR *, 6R * 16aR *) - 6-Hydroxy-3 - (((2-nitrophenyl) sulfonyl) hexahydro-2H-cyclopenta [d] oxazol-2-one

[00723] To a solution of tert-butyl (1R *, 2S *, 5S *) - 6-oxabicyclo [3.1.0] hexan-2-yl ((2-nitrophenyl) sulfonyl) carbamate (2.0 g, 5.10 mmols) in MeOH (40 ml) Amberlist 15 (4.0 g) was added and the resulting suspension was stirred for 1.5 h at 25 ° C. The reaction mixture was filtered and concentrated. The title compound was obtained after purification by flash chromatography (heptane-EtOAc 90:10 —► EtOAc) as a beige solid (1.24 g, 73%): TLC (heptane / EtOAc 1: 2) Rf = 0.36; tR = 0.80 min (UPLC 1), tR = 0.77 min (LC-MS 3); ESI-MS: 346 [M + NH4] + (LC-MS 3). Step 22.6: tert-butyl (1R *, 2S *, 5S *) - 6-oxabicyclo [3.1.0lhexan-2-yl ((2-nitrophenyl) sulfonyl) carbamate

[00724] To a suspension of cyclopent-2-en-1-yl ((2-nitrophenyl) sulfonyl) tert-butyl carbamate (2.75 g, 7.46 mmols) and NaHCOs (1.254 g, 14.93 mmols ) in CH2 Cl2 (60 mL) was added in one portion meta-chloroperoxybenzoic acid (2.58 g, 14.93 mmols). The resulting reaction mixture was stirred overnight at RT. The reaction mixture was diluted with CH2 Cl2 and washed with 20% aqueous Na2Sθ3 solution, saturated NaHCO3 solution and water. The organic phase was dried over MgSO4 and concentrated. The title compound was obtained after crystallization from EtOAc as white crystals (2.01 g, 68%): TLC (heptane-EtOAc 1: 1) Rf = 0.48; tR = 1.20 min (UPLC 1), tR = 1.12 min (LC-MS 3); ESI-MS: 329 [M-isobutylene] + (LC-MS 3). Step 22.7: tert-butyl (cyclopent-2-en-1-yl ((2-nitrophenyl) sulfonyl) carbamate

[00725] To a suspension of triphenylphosphine (3.09 g, 11.77 mmol), tert-butyl 2-nitrophenylsulfonylcarbamate (3.40 g, 11.23 mmol) and cyclopent-2-enol (0.900 g, 10.70 mmols) in toluene (60 ml) diethylazodicarboxylate (1.948 ml, 12.30 mmols) was added by dropping at -20 ° C. The reaction mixture was stirred at -20 ° C for 2 h followed by 3 h at 0 ° C. The reaction mixture was concentrated and the title compound was obtained after purification by flash chromatography (3: 1 hepatic / EtOAc 95: 5) as a white solid (2.79 g, 67%): tR = 1, 34 min (UPLC 1), t R = 1.24 min (LC-MS 3); ESI-MS: 386 M + NH4] + (LC-MS 3). Example 22A: first enantiomer eluted in Chiralpak AD from (3aR, 6R, 6aR) - and (3aS16S, 6aS) - (2'-Amino-2-morpholino-4, - (trifluoromethyl) - [4,5'-bipyrimidin] -6-yl) -6-hydroxyhexa-hydro-2H-cyclopenta [d] oxazol-2-one
[00726] Absolute stereochemistry not determined.
[00727] The title compound was obtained after preparative chiral HPLC separation of the racemic product of Example 22. (Column: Chiralpak AD 20pm 5 x 500 mm. Flow 70 mL / min. Heptane / EtOH / DEA 20: 80: 0.01 ). tR: 17.7 min (Column: Chiralpak AD-H, 4.6 x 250 mm. Flow 1.2 ml / min. heptane / EtOH 70:30). Example 22B: second enantiomer eluted in Chiralpak AD of (3aR, 6R, 6aR) - and (3aS, 6S, 6aS) - (2'-Amino-2-morpholino-4, - (trifluoromethyl) - [4,5'- bipyrimidinl-6-yl) -6-hydroxyhexa-hydro-2H-cyclopenta [d] oxazol-2-one
[00728] Absolute stereochemistry not determined.
[00729] The title compound was obtained after preparative chiral HPLC separation of the racemic product of Example 22. (Column: Chiralpak AD 20pm 5 x 500 mm. Flow 70 mL / min. Heptane / EtOH / DEA 20: 80: 0.01 ). IR: 23.3 min (Column: Chiralpak AD-H, 4.6 x 250 mm. Flow 1.2 ml / min. Heptane / EtOH 70:30). Example 23: (4S, 5R) -3- (2, -Amino-2-morpholino-4, - (trifluoromethyl) - [4,5'-bipyrimidin] -6-yl) -5- (2-hydroxyethyl) - 4-methyloxazolidin-2-one

[00730] To a solution of (4S, 5R) -3- (2'-amino-2-morpholino-4'- (trifluoromethyl) - [4,5'-bipyrimidin] -6-yl) -5- (2 - ((tert-butyldiphenylsilyl) oxy) ethyl) -4-methyloxazolidin-2-one (2.1 g, 3 mmols) in THF (20 mL), was added by dripping 1M TBAF in THF (3 mL, 3 mmols) at 0 ° C. The reaction mixture was stirred for 1 h at 0 ° C before evaporation. The residue was purified by flash chromatography (hexane / EtOAc / MeOH 90: 10: 1 0: 100: 10). The purified product was recrystallized from MeOH to provide the title compound as a white solid (1.17 g, 83%): ÍR = 0.80 min (UPLC 1), tR = 0.82 min (LC-MS 3) ; ESI-MS: 470 [M + H] + (LC-MS 3). Step 23.1: (4S, 5R) -3- (2, -Amino-2-morpholino-4, - (trifluoromethyl) - [4,5'- bipyrimidin] -6-yl) -5- (2 - ((tert -butyldiphenylsilyl) oxy) ethyl) -4-methyloxazolidin-2-one

[00731] The title compound was prepared in analogy to the procedure described for Example 22.1 from 4S, 5R) -5- (2 - (((tert-butyldiphenylsilyl) oxy) ethyl) -3- (6-chlorine -2-morpholinopyrimidin-4-yl) -4-methyloxazolidin-2-one and intermediate B to provide the title compound after crystallization in MeOH: tR = 1.72 min (UPLC 1), ÍR = 1.55 min ( LC-MS 3); ESI-MS: 708 [M + H] + (LC-MS 3). Step 23.2: (4S, 5R) -5- (2 - ((tert-butyldiphenylsilyl) oxy) ethyl) -3- (6-chloro-2-morpholinopyrimidin-4-yl) -4-methyloxazolidin-2-one

[00732] The title compound was prepared in analogy to the procedure described for step 21.1 from a 4: 1 mixture of the di-astereoisomers (4S, 5R) - and (4S, 5S) - of 5- (2 - (((tert-butyldiphenylsilyl) oxy) ethyl) -3- (6-chloro-2-morpholinopyrimidin-4-yl) -4-methyloxazolidin-2-one and intermediate A to provide, after removal of the diastereoisomer (4S , 5S) by the two recrystallizations in THF / MeOH only the diastereoisomer (4S, 5R) of the title compound: ÍR = 1.88 min (UPLC 1), ÍR = 1.64 min (LC-MS 3); ESI-MS: 581, 583 [M + H] + (LC-MS 3); 1H NMR (400 MHz, DMSO-d6): δ 1.08 (s, 9H), 1.36 (d, 3H), 2.02 (m, 2H), 3.70-3.90 (m, 10H ), 4.82 (m, 2H), 7.40-7.50 (m, 6H), 7.51 (s, 1H), 7.67 (m, 4H). Step 23.3: (4S, 5R) - and (4S, 5S) -5- (2 - ((tert-butyldiphenylsilyl) oxy) ethyl) -4-methyloxazolidin-2-one

[00733] To a solution of a 4: 1 mixture of the diastereoisomers (4S, 5R) - and (4S, 5S) of 5- (2 - ((tert-butyldiphenylsilyl) oxy) ethyl) -3- (4-methoxybenzyl) -4-methyloxazolidin-2-one (4.1 g, 7.8 mmols) in acetonitrile (40 mL) a solution of (NH4) 2Ce (NOs) 6 (10.71 g, 19.5 mmols) was added ) in H2O (20 mL) at 0 ° C. The reaction mixture was stirred for 4 h at 0-5 ° C. The mixture was added to ice water and the product extracted with EtOAc. The combined extracts were washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The title compound was obtained after purification by flash chromatography (heptane / EtOAc 10: 1 -> EtOAc) as a 4: 1 mixture of diastereoisomers (2.2 g, 71%): TLC (hexane-EtOAc 1: 1) Rf = 0.23; tR = 1.47 min (UPLC 1), tR = 1.33 min (LC-MS 3); ESI-MS: 401 [M + NH4] + (LC-MS 3). Step 23.4: (4S, 5R) - and (4S, 5S) -5- (2 - ((tert-butyldiphenylsilyl) oxy) ethyl) -3- (4-methoxybenzyl) -4-methyloxazolidin-2-one

[00734] To a solution of a 4: 1 mixture of the diastereoisomers (4S, 5R) - and (4S, 5S) of 5- (2-hydroxyethyl) -3- (4-methoxybenzyl) -4-methyloxazolidin-2-one (2.65 g, 10 mmols) in DMF (30 ml) was added imidazole (1.73 g, 25 mmols) and TBDPSCI (3.57 g, 13 mmols) at 0-5 ° C. The reaction mixture was allowed to warm to RT and was stirred overnight at RT. The reaction mixture was concentrated and the residual oil was dissolved in TBME and washed with an aqueous solution of KHSO410%, H2O, saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The title compound was obtained after purification by flash chromatography (heptane / EtOAc 20: 1 -> 2: 1) as a 4: 1 mixture of diastereoisomers (4.18 g, 80%): TLC (hexane / EtOAc 3: 1) Rf = 0.27; tR = 1.70 min (UPLC 1), tR = 1.52 min (LC-MS 3); ESI-MS: 526 [M + Na] + (LC-MS 3). Step 23.5: (4S, 5R) - and (4S, 5S) -5- (2-hydroxyethyl) -3- (4-methoxybenzyl) -4-methyloxazolidin-2-one

[00735] A 4: 1 mixture of (4S, 5R) - and (4S, 5S) -5-allyl 3- (4-methoxybenzyl) -4-methyloxazolidin-2-one (2.67 g, 10 mmol) in 2: 1 CH2 Cl2-MeOH (40 mL) was ozonized at -78 ° C. After completing the ozone formation, NaBH4 (0.57 g, 15 mmols) was added and the reaction mixture was allowed to warm to RT and stirred for 2 h at RT. The reaction mixture was added to a 20% aqueous K2CO3 solution and the product was extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound as a light yellow oil (2.65 g, 99%): TLC (EtOAc) Rf = 0.28; tR = 0.68 min (UPLC 1), tR = 0.69 min (LC-MS 3); ESI-MS: 266 [M + H] + (LC-MS 3). Step 23.6: (4S, 5R) - and (4S, 5S) -5-allyl-3- (4-methoxybenzyl) -4-methyloxazolidin-2-one

[00736] To a solution of a 4: 1 mixture of benzyl (((2S, 3R) -3-hydroxyhex-5-en-2-yl) (4-methoxybenzyl) carbamate and ((2S, 3S) - 3- benzyl hydroxyhex-5-en-2-yl) (4-methoxybenzyl) carbamate (3.55 g, 9.5 mmols) in THF (60 mL) was added under argon at -50 ° C a 1M NaHMDS solution in THF (10.5 ml). After stirring the reaction mixture for 0.5 h at -40 ° C, the mixture was added to an ice cold 10% KHSO4 solution and the product was extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated. The title compound was obtained after purification by flash chromatography (10: 1 hexane / EtOAc -> 1: 1) as a colorless oil (2.4 g, 97%): TLC (1: 1 hexane / EtOAc) Rf = 0.42; tR = 1.03 min (UPLC 1), tR = 0.99 min (LC-MS 3); ESI-MS: 262 [M + H] + (LC-MS 3); 1H NMR (400 MHz, DMSO-d6): δ 1.06 (d, 2.4H), 1.13 (d, 0.6H), 2.30-2.40 (m, 2H), 3.25 (m, 0.2H), 3.66 (m, 0.8H, accentuated NOE to signal to 4.54), 3.75 (s, 3H), 4.07 (d, 1H), 4, 10 (m, 0.2H), 4.48 (d, 1H), 4.54 (m, 0.8H), 5.05-5.20 (m, 2H), 5.23 (m, 0, 2H), 5.78 (m, 0.8H), 6.92 (d, 2H), 7.22 (d, 0.4H), 7.24 (d, 1.6H). Step 23.7: (2S.3R) - e (2S, 3S) -benzyl 4-methoxybenzyl (1-oxopropan-2-iDcarbamate

[00737] To a solution of (S) -benzyl 4-methoxybenzyl (1-oxopropan-2-yl) carbamate (3.86 g, 10 mmol) in THF (30 mL) was added zinc powder (1.64 g, 25 mmols), saturated aqueous NH4 Cl1% solution (5 ml) and allyl bromide (2.2 ml, 25 mmols) and the reaction mixture was stirred for 1 h at 25-30 ° C. The reaction mixture was diluted with H2O and the product was extracted into EtOAc. The combined extracts were washed with an aqueous solution of 10% NH4 Cl, H2O, NaHCOs and brine, dried over MgSO4, filtered and concentrated. The title compound was obtained after purification by flash chromatography (hexane / EtOAc 20: 1 2: 1) as a colorless oil (3.5 g, 97%): tR = 1.25 min and 1.27 min (UPLC 1) (4: 1 mixture of diastereoisomers (2S, 3R) - and (2S, 3S)), TLC (1: 1 hexane / EtOAc) Rf = 0.51; tR = 1.68 min and 1.69 min (LC-MS 3); ESI-MS: 370 [M + H] + (LC-MS 3). Step 23.8: (S) -benzyl 4-methoxybenzyl (1-oxopropan-2-yl) carbamate

[00738] To a solution of (S) -benzyl (1-hydroxypropan-2-yl) (4-methoxybenzyl) carbamate (11.8 g, 35.5 mmols) in CH2 Cl2 was added NaHCOa (3.28 g, 39 mmols), KBr (0.25 g, 2.1 mmols) and TEMPO 0.168 g, 1.07 mmols). The reaction mixture was cooled to 0-5 ° C and 5% NaCIO aqueous solution (85 mL, 71 mmols) was added within 30 min. After stirring for 1 h at 0-5 ° C, the reaction mixture was added to a Na2S2Ü3 solution and the product was extracted with EtOAc. The combined extracts were washed with aqueous NaH2PO4, H2O and brine, dried over MgSO4, filtered and concentrated to provide the title compound as a yellow oil (11.2 g, 96%): TLC (hexane / EtOAc 1: 1 ) Rf = 0.55; tR = 1.29 min (UPLC 1), tR = 1.15 min (LC-MS 3); ESI-MS: 328 [M + H] + (LC-MS 3). Step 23.10: (S) - Benzyl (1-hydroxypropan-2-yl) (4-methoxybenzyl) carbamate

[00739] To a solution of (S) -2 - (((benzyloxy) carbonyl) (4-methoxybenzyl) amino) propanoic acid [439589-23-8] (16 g, 41.9 mmol) in THF (150 mL ) was slowly added under argon boron dimethylsulfide (8.4 mL, 84 mmols) at 0-5 ° C. The reaction mixture was stirred for 1 h at 0-5 ° C followed by 3 h at 40-45 ° C. The excess boron was destroyed by the careful addition of MeOH and the reaction mixture was evaporated 3x with 200 ml of MeOH and 2x with CHCh. The title compound was obtained after drying as a colorless oil (13.7 g, 99%): TLC (hexane / EtOAc 1: 1) Rf = 0.22; IR = 1.06 min (UPLC 1), IR = 1.02 min (LC-MS 3); ESI-MS: 330 [M + H] + (LC-MS 3). Example 24: first elute the diastereoisomer in LC-MS 3 of (4S, 5R) -3- (2, -amino-2-morpholino-4 '- (trifluoromethyl) - [4,5, -bipyrimidin] -6-yl ) - 5 - ((R) -2-hydroxypropyl) -4-methyloxazolidin-2-one
[00740] Absolute stereochemistry of the undetermined 2-hydroxypropyl portion, arbitrarily designated (R) configuration.

[00741] The title compound was prepared in analogy to the procedure described for Example 23 from (4S, 5R) -3- (2'-amino-2-morpholino-4 '- (trifluoromethyl) - [4 , 5'-bipyrimidin] -6-yl) -5 - ((R) -2 - ((tert-butyldiphenylsilyl) oxy) propyl) -4-methyloxazolidin-2-one and TBAF to provide after purification by flash chromatography ( hexane / EtOAc 5: 1 -> EtOAc / MeOH 10: 1) and recrystallization from MeOH the title compound as a white solid: TLC (EtOAc) Rf = 0.50; IR = 0.88 min (LC-MS 3); ESI-MS: 484 [M + H] + (LC-MS 3). Step 24.1: (4S.5R) -3- (2, -amino-2-morpholino-4, - (trifluoromethyl) - [4,5, - bipyrimidin] -6-yl) -5 - ((R) -2 - (((tert-butyldiphenylsilyl) oxy) propyl) -4-methyloxazolidin-2-one
[00742] Absolute stereochemistry of the undetermined protected 2-hydroxypropyl moiety, configuration (R) arbitrarily designated.

[00743] The title compound was prepared in analogy to the procedure described for step 22.1 from (4S, 5R) -5 - ((R) -2 - ((tert-butyldiphenylsilyl) oxy) propyl) -3 - (6-chloro-2-morpholinopyrimidin-4-yl) -4-methyloxazolidin-2-one and intermediate B to provide after purification by flash chromatography (20: 1 EtOAc hexane / EtOAc) the title compound as a light yellow foam: TLC (hexane / EtOAc 1: 1) Rf = 0.45; tR = 1.57 min (LC-MS 3); ESI-MS: 722 [M + H] + (LC-MS 3). Step 24.2: (4S, 5R) -5 - ((R) -2 - ((tert-butyldiphenylsilyl) oxy) propyl) -3- (6-chloro-2-morpholinopyrimidin-4-yl) -4-methyloxazolidin-2 -one
[00744] Absolute stereochemistry of the undetermined protected 2-hydroxypropyl portion, configuration (R) arbitrarily designated.

[00745] The title compound was prepared in analogy to the procedure described for step 21.1 from (4S, 5R) -5 - ((R) -2 - ((tert-butyldiphenylsilyl) oxy) propyl) -4 -methyloxazolidin-2-one and intermediate A to provide after purification by flash chromatography (hexane / EtOAc 20: 1 -> 3: 1) the title compound as a colorless oil: TLC (hexane / EtOAc 1: 1) Rf = 0.65; t R = 1.67 min (LC-MS 3); ESI-MS: 595, 597 [M + H] + (LC-MS 3). Step 24.3: (4S, 5R) -5 - ((R) -2 - ((tert-butyldiphenylsilyl) oxy) propyl) -4-methyloxazolidin-2-one Absolute stereochemistry of the non-terminated protected 2-hydroxypropyl portion, configuration (R) arbitrarily designated.

[00746] The title compound was prepared in analogy to the procedure described for step 23.3 from (4S, 5R) -5 - ((R) -2 - ((tert-butyldiphenylsilyl) oxy) propyl) -3 - (4-methoxybenzyl) -4-methyloxazolidin-2-one to provide after purification by flash chromatography (hexane / EtOAc 20: 1 -> EtOAc) the title compound as a colorless oil: TLC (hexane / EtOAc 1 : 1) Rf = 0.28; tR = 1.38 min (LC-MS 3); ESI-MS: 415 [M + NH4] + (LC-MS 3). Step 24.4: (4S, 5R) -5 - ((R) -2 - ((tert-butyldiphenylsilyl) oxy) propyl) -3- (4-methoxybenzyl) -4-methyloxazolidin-2-one
[00747] Absolute stereochemistry of the undetermined protected 2-hydroxypropyl portion, arbitrarily designated (R) configuration.

[00748] The title compound was prepared in analogy to the procedure described for step 23.4 from (4S, 5R) -5 - ((R) -2-hydroxypropyl) -3- (4-methoxybenzyl) -4 -methyloxazolidin-2-one (contaminated with 15% of the diastereoisomer eluted first (2S, 4S, 5R) from step 24.5) to provide after purification by flash chromatography (20: 1 EtOAc hexane / EtOAc) the title compound as an oil colorless: TLC (3: 1 hexane / EtOAc) Rf = 0.26; t R = 1.55 min (LC-MS 3); ESI-MS: 540 [M + Na] + (LC-MS 3). Step 24.5: (4S, 5R) -5 - ((S) - and (4S, 5R) -5 - ((R) -2-hydroxypropyl) -3- (4-methoxybenzyl) -4-methyloxazolidin-2-one
[00749] Absolute stereochemistry of the 2-hydroxypropyl portion after ketone reduction has not been determined, the configuration (S) arbitrarily assigned to the first product eluted from the diastereoisomer (4S, 5R, 5S).
[00750] First product eluted from the diastereoisomer (4S, 5R, 5S):

[00751] Second eluted product, mixture of diastereoisomer (2R, 4S, 5R) (configuration (2R) arbitrarily assigned to the 2-hydroxypropyl portion):

[00752] Contaminated with the first eluted diastereoisomer (4S, 5R, 5S):

[00753] The title compound was prepared in analogy to the procedure described for step 23.5 from a 3: 1 mixture of diastereoisomer (4S, 5R) - and (4S, 5S) - of 3- (4-methoxybenzyl ) -4-methyl-5- (2-methylalyl) oxazolidin-2-one to provide, after multiple separations of the 3: 3: 1: 1 mixture of isomers by flash chromatography (RediSep Rf Gold silica gel; hexane / EtOAc 1: 1 -> EtOAc and toluene / EtOAc 3: 1 -> EtOAc), the two individual smaller diastereoisomers (2S, 4S, 5S) - and (2R, 4S, 5S) - and the two individual larger diastereoisomers (2S, 4S , 5R) - and (2R, 4S, 5R) - as colorless oils:
[00754] First eluted diastereoisomer (2S, 4S, 5R) - of the title compound (designated arbitrarily as configuration (2S) - for the 2-hydroxypropyl moiety): TLC (EtOAc) Rf = 0.39; tR = 0.752 min (UPLC 1); tR = 0.76 min (LC-MS 3); ESI-MS: 280 [M + H] + (LC-MS 3); 1H NMR (400 MHz, CDCh): δ 1.12 (d, 3H), 1.28 (d, 3H), 1.5-1.63 (m, 1H), 1.81 (m, 1H), 1.90 (d, 1H), 3.68 (m, 1H), 3.82 (s, 3H), 4.03 (d, 1H), 4.14 (m, 1H), 4.60 (ddd , 1H), 4.79 (d, 1H), 6.89 (d, 2H), 7.22 (d, 2H).
[00755] First eluted diastereoisomer (2R, 4S, 5R) - of the title compound (arbitrarily designated as configuration (2R) - for the 2-hydroxypropyl portion) contaminated with 15% of the first eluted diastereoisomer (2S, 4S, 5R) - : TLC (EtOAc) Rf = 0.35; tR = 0.742 min and 0.752 min (UPLC 1); tR = 0.75 min and 0.76 min (LC-MS 3); ESI-MS: 280 [M + H] + (LC-MS 3); 1H NMR (400 MHz, CDCh): δ 1.12 (d, 3H), 1.28 (d, 3H), 1.50-1.64 (m, 1H), 1.81 (m, 0.15H ), 1.90 (d, 0.15H), 1.94 (m, 0.85H), 2.21 (d, 0.85H), 3.67 (m, 1H), 3.82 (s, 3H), 4.01 (m, 1H), 4.13 (m, 1H), 4.73 (m, 0.85H), 4.79 (d, 0.15H), 4.80 (d, 1H ), 6.90 (d, 2H), 7.22 (d, 2H). Step 24.6: diastereoisomers (4S.5R) - and (4S, 5S) - of 3- (4-methoxybenzyl) -4-methyl-5- (2-methylalyl) oxazolidin-2-one

[00756] The title compound was prepared in analogy to the procedure described for step 23.6 from a 3: 1 mixture of the di-astereoisomers (2S, 3R) - and (2S, 3S) - of ((2S) -3-hydroxy-5-methylhex-5-en-2-yl) (4-methoxybenzyl) benzyl carbamate to provide after purification by flash chromatography (hexane / EtOAc 20: 1 -> 1: 1) the compound of the title as a 3: 1 mixture of diastereoisomers (4S, 5R) - and (4S.5S) -: tR = 1.112 min (UPLC 1); t R = 1.05 min (LC-MS 3); ESI-MS: 276 [M + H] + (LC-MS 3); 1H NMR (400 MHz, CDCh): δ 1.13 (d, 2.2H), 1.20 (d, 0.8H), 1.76 (s, 0.8H), 1.80 (s, 2 , 2H), 2.23 (ddd, 0.25H), 2.27 (dd, 0.75H), 2.39 (dd, 0.25H) 2.46 (dd, 0.75H), 3.28 (m, 0.25H), 3.68 (m, 0.75H), 3.83 (s, 3H), 3.99 (d, 0.75H), 4.04 (d, 0.35H), 4.14 (m, 0.25H), 4.62 (m, 0.75H), 4.70-4.90 (m, 4H), 6.90 (d, 2H), 7.25 (d, 2H). Step 24.7: diastereoisomers (2S, 3R) - and (2S, 3S) - of (3-hydroxy-5-methylhex-5-en-2-yl) (4-methoxybenzyl) benzyl carbamate

[00757] The title compound was prepared in analogy to the procedure described for step 23.7 from (S) -benzyl 4-methoxybenzyl (1-oxopropan-2-yl) carbamate and 3-bromo-2-methylprop -1-ene to provide the title compound as a 3: 1 mixture of diastereoisomers (2S, 3R) - and (2S, 3S) -: tR = 1.322 min (major isomer) and 1.329 min (minor isomer) ( UPLC 1); tR = 1.23 min (major isomer) and 1.24 min (minor isomer) (LC-MS 3); ESI-MS: 384 [M + H] + (LC-MS 3). Example 25: second LC MS 3 elution product which is a 9: 1 mixture of (4S, 5R) - and (4S, 5S) -3- (2, -amino-2-morpholino-4 '- (trifluoromethyl) - [4,5'-bipyrimidin] -6-yl) -5 - ((S) -2-hydroxypropyl) -4-methyloxazolidin-2-one
[00758] Absolute stereochemistry of the undetermined 2-hydroxypropyl portion, arbitrarily designated (S) configuration.

[00759] The title compound was prepared in analogy to the procedure described for Example 23 from an 8: 1 mixture of (4S, 5R) - and (4S, 5S) -3- (2'-amino- 2-morpholino-4 '- (trifluoromethyl) - [4,5'- bipyrimidin] -6-yl) -5 - ((S) -2 - ((tert-butyldiphenylsilyl) oxy) propyl) -4-methyloxazolidin-2 -one and TBAF to provide after purification by flash chromatography (hexane / EtOAc 5: 1 -> EtOAc / MeOH 10: 1) and recrystallization with MeOH the title compound as a white solid: TLC (EtOAc) Rf = 0 , 50; ÍR = 0.87 min (diastereoisomer (4S, 5S) - minor) and 0.89 min (major diastereoisomer (4S, 5R) -) (LC-MS 3); ESI-MS: 484 [M + H] + (LC-MS 3). Step 25.1: (4S, 5R) - e (4S, 5S) -3- (2'-amino-2-morpholino-4'- (trifluoromethyl) - [4,5, -bipyrimidin] -6-yl) -5 - (((S) -2 - (((tert-butyldiphenylsilyl) oxy) propyl) -4-methyloxazolidin-2-one
[00760] Absolute stereochemistry of the undetermined protected 2-hydroxypropyl moiety, configuration (S) arbitrarily designated.

[00761] The title compound was prepared in analogy to the procedure described for step 22.1 from a 7: 1 mixture of (4S, 5R) - and (4S, 5S) -5 - ((R) -2 - (((tert-butyldiphenylsilyl) oxy) propyl) -3- (6-chloro-2-morpholinopyrimidin-4-yl) -4-methyloxazolidin-2-one and intermediate B to provide after purification by flash chromatography (hexane / EtOAc 20: 1 EtOAc), the title compound as an 8: 1 mixture of diastereoisomers (4S, 5R) - and (4S, 5S) -: TLC (hexane / EtOAc 1: 1) Rf = 0.45; t R = 1.58 min (LC-MS 3); ESI-MS: 722 [M + H] + (LC-MS 3). Step 25.2: (4S.5R) - e (4S15S) -5 - ((S) -2 - ((tert-butyldiphenylsilyl) oxy) propyl) - 3- (6-chloro-2-morpholinopyrimidin-4-yl) - 4-methyloxazolidin-2-one
[00762] Absolute stereochemistry of the undetermined protected 2-hydroxypropyl portion, configuration (S) arbitrarily designated.

[00763] The title compound was prepared in analogy to the procedure described for step 21.1 from a 7: 1 mixture of (4S, 5R) - and (4S, 5S) -5 - ((S) -2 - (((tert-butyldiphenylsilyl) oxy) propyl) -4-methyloxazolidin-2-one and intermediate A to provide after purification by flash chromatography (hexane / EtOAc 20: 1 —► 3: 1) and crystallization with MeOH / THF, the title compound from a 7: 1 mixture of diastereoisomers (4S, 5R) - and (4S, 5S) -: TLC (hexane / EtOAc 1: 1) Rf = 0.65; t R = 1.67 min (LC-MS 3); ESI-MS: 595, 597 [M + H] + (LC-MS 3). Step 25.3: (4S.5R) - e (4S, 5S) -5 - ((S) -2 - ((tert-butyldiphenylsilyl) oxy) propyl) - 4-methyloxazolidin-2-one
[00764] Absolute stereochemistry of the protected 2-hydroxypropyl portion not determined, configuration (S) arbitrarily determined.

[00765] The title compound was prepared in analogy to the procedure described for step 23.3 from a 7: 1 mixture of (4S, 5R) - and (4S, 5S) -5 - ((S) -2 - (((tert-butyldiphenylsilyl) oxy) propyl) -3- (4-methoxybenzyl) -4-methyloxazolidin-2-one to provide after purification by flash chromatography (hexane / EtOAc 20: 1 -> 2: 1) the title compound as a colorless oil as a 10: 1 mixture of diastereoisomer (4S, 5R) - and (4S, 5S) -: TLC (hexane / EtOAc 1: 1) Rf = 0.30; tR = 1.38 min (LC-MS 3); ESI-MS: 415 [M + NH4] + (LC-MS 3). Step 25.4: (4S.5R) - e (4S, 5S) -5 - ((S) -2 - ((tert-butyldiphenylsilyl) oxy) propyl) - 3- (4-methoxybenzyl) -4-methyloxazolidin-2- ona
[00766] Absolute stereochemistry of the protected 2-hydroxypropyl portion not determined, configuration (S) arbitrarily determined.

[00767] The title compound was prepared in analogy to the procedure described for step 23.4 from a 7: 1 mixture of (4S, 5R) - and (4S, 5S) -5 - ((S) -2 -hydroxypropyl) -3- (4-methoxybenzyl) -4-methyloxazolidin-2-one prepared in step 24.5 to provide after purification by flash chromatography (hexane / EtOAc 20: 1 EtOAc) the title compound as a 7: 1 mixture diastereoisomer (4S, 5R) - and (4S, 5S) -: TLC (hexane / EtOAc 3: 1) Rf = 0.26; t R = 1.56 min (LC-MS 3); ESI-MS: 540 [M + Na] + (LC-MS 3). Example 26: (4S.5R) - e (4S, 5S) -3- (2, -amino-2-morpholino-4'- (trifluoromethyl) - [4,5, -bipyrimidin] -6-yl) -5 - (2-hydroxy-2-methylpropyl) -4-methyloxazolidin-2-one

[00768] The title compound was prepared in analogy to the procedure described for step 22.1 from a 5: 1 mixture of (4S, 5R) - and (4S, 5S) -3- (6-chloro-2 -morpholinopyrimidin-4-yl) -5- (2-hydroxy-2-methylpropyl) -4-methyloxazolidin-2-one and intermediate B to provide after purification by flash chromatography (hexane / EtOAc / MeOH 90:10: 1 10: 100: 10) and recrystallization with MeOH, the title compound as a white solid and to a 7: 1 mixture of diastereoisomer (4S, 5R) - and (4S, 5S) -: TLC (EtOAc) Rf = 0.43; tR = 0.93 min (LC-MS 3); ESI-MS: 498 [M + H] + (LC-MS 3). Step 26.1: (4S.5R) - e (4S, 5S) -3- (6-chloro-2-morpholinopyrimidin-4-yl) -5- (2-hydroxy-2-methylpropyl) -4-methyloxazolidin-2- ona

[00769] The title compound was prepared in analogy to the procedure described for step 21.1 from a 5: 1 mixture of (4S, 5R) - and (4S, 5S) -5 - ((S) -2 - ((tert-butyldiphenylsilyl) oxy) propyl) -4-methyloxazolidin-2-one and intermediate A to provide after purification by flash chromatography (hexane / EtOAc 10: 1 EtOAc) the title compound as a light yellow foam and as a 5: 1 mixture of diastereoisomers (4S, 5R) - and (4S, 5S) -: TLC (EtOAc / MeOH 10: 1) Rf = 0.55; t R = 1.02 min (LC-MS 3); ESI-MS: 371, 373 [M + H] + (LC-MS 3). Step 26.2: (4S.5R) - e (4S, 5S) -5- (2-hydroxy-2-methylpropyl) -4-methyloxazolidin-2-one

[00770] The title compound was prepared in analogy to the procedure described for step 23.3 from a 5: 1 mixture of (4S, 5R) - and (4S, 5S) -5- (2-hydroxy-2 -methylpropyl) -3- (4-methoxybenzyl) -4-methyloxazolidin-2-one to provide after purification by flash chromatography (hexane-EtOAc 1: 1 -> EtOAc-MeOH 5: 1) the title compound as a colorless oil as a 5: 1 mixture of diastereoisomers (4S, 5R) - and (4S, 5S) -: TLC (EtOAc / MeOH 10: 1) Rf = 0.40; tR = 0.41 min (LC-MS 3); ESI-MS: 174 [M + H] + (LC-MS 3). Step 26.3: (4S.5R) - e (4S, 5S) -5- (2-hydroxy-2-methylpropyl) -3- (4-methoxybenzyl) -4-methyloxazolidin-2-one

[00771] To a solution of a 3: 1 mixture of 2 - ((4S, 5R) -3- (4-methoxybenzyl) -4-methyl-2-oxoxazolidin-5-yl) methyl acetate and 2- (( 4S, 5S) -3- (4-methoxybenzyl) -4-methyl-2-oxoxazolidin-5-yl) methyl acetate (2.0 g, 6.82 mmol) in THF (50 mL), was added slowly under argon a 3M solution of methylmagnesium chloride in THF (6.82 mL, 20.46 mmols) at -78 ° C. After the addition, the reaction mixture was allowed to warm up to RT. After adding a 10% aqueous NH4 Cl solution, the product was extracted with EtOAc. The combined extracts were washed with H2O, dried over MgSO4, filtered and concentrated to provide the title compound after purification by flash chromatography (hexane / EtOAc 20: 1 EtOAc) as a colorless oil (1.2 g, 59%, 3: 1 mixture of diastereoisomer (4S, 5R) - and (4S, 5S) -): TLC (CH2 Cl2 / MeOH 10: 1) Rf = 0.43; tR = 0.80 min and 0.81 min (LC-MS 3); ESI-MS: 294 [M + H] + (LC-MS 3); 1H NMR (400 MHz, CDCh): δ 1.12 (d, 2.25H), 1.22 (d, 0.75), 1.32 (s, 1.5H), 1.34 (s, 4 , 5H), 1.68 (dd, 1H), 1.86 (dd, 0.25H), 1.93 (dd, 0.75H), 3.23 (m, 0.25H), 3.64 ( m, 0.75H), 3.83 (s, 3H), 3.99 (d, 0.75H), 4.04 (d, 0.25H), 4.26 (d, 0.25H), 4 .72 (d, 0.25H), 4.73 (m, 0.75H), 4.80 (d, 0.75H), 6.89 (d, 0.5H), 6.90 (d, 1 , 5H), 7.23 (d, 0.5H), 7.24 (1.5H). Step 26.4: 2 - (((4S, 5R) -3- (4-methoxybenzyl) -4-methyl-2-oxoxazolidin-5-methyl methyl acetate and 2 - ((4S, 5S) -3- (4-methoxybenzyl) -4-methyl-2-oxoxazolidin-5-yl) methyl acetate

[00772] To a suspension of a 3: 1 mixture of (3R, 4S) - and (3S, 4S) -methyl 3-hydroxy-4 - ((4methoxybenzyl) amino) pentanoate (4.1 g, 10.74 mmols ) in CH2 Cl2 (80 ml) DIEA (8.44 ml, 48.3 mmols) was added and at 0 ° C a solution of (bis (trichloromethyl) carbonate (2.389 g, 8.05 mmols) dissolved in CH2 Cl2 (10 After stirring for 0.5 h in RT, the reaction mixture was added to a saturated solution of NaHCOs and the product was extracted with CH2 Cl2.The combined extracts were washed with H2O, dried over MgSO4, filtered and concentrated to provide the title compound after purification by flash chromatography (hexane / EtOAc 20: 1 EtOAc) as a light yellow foam (2.02 g, 63%, 3: 1 mixture of diastereoisomers (4S, 5R) - and ( 4S.5S)): TLC (toluene / EtOAc 1: 1) Rf = 0.47; tR = 0.84 min (LC-MS 3); ESI-MS: 294 [M + H] + (LC-MS 3 ); 1H NMR (400 MHz, CDCh): δ 1.11 (d, 2.25H), 1.27 (d, 0.75H), 2.57 (dd, 0.25H), 2.67 (dd, 0.75H), 2.75 (dd, 0.25H), 2.81 (dd, 0.75H), 3.34 (m, 0.25H), 3.70 (s, 0.75H), 3.73 (s, 2.25H), 3.77 (m, 0.75H), 3.83 (s, 3H), 3.99 (d, 0.75H), 4.04 (d, 0.25H), 4.44 (m, 0.25H), 4.75 (d, 0.25H), 4.78 (d, 0.75H), 4.88 (m, 0.75H), 6.90 (d, 2H), 7.22 (d, 0.5H), 7.23 (d, 1.5H). Step 26.5: (3R.4S) - and (3S, 4S) -Methyl 3-hydroxy-4 - ((4-methoxybenzyl) amino) pentanoate

[00773] To a hydrochloride suspension of (3R, 4S) -methyl 4-amino-3-hydroxypentanoate [111061-25-7] (2.17 g, 11.8 mmol) in CH2 Cl2 (60 mL) and MeOH ( 60 ml) NaOAc (1.357 g, 16.54 mmols) was added and after 10 min of p-anisaldehyde stirring (1.37 ml, 11.2 mmols) and a molecular sieve (2 g). The reaction mixture was stirred for 16 h at RT. After adding 2 ml of AcOH, NaBHsCN (1.11 g, 17.7 mmols) was added in portions over a period of 30 min. After stirring for an additional 30 min in RT, the reaction mixture was filtered, the filtrate acidified with aqueous 4N HCI and evaporated to dryness. The residue was washed first with Et2θ, then suspended in CHLCh / MeOH 1: 1 and the inorganic material was filtered. The filtrate was concentrated to provide the title compound after drying at 50 ° C for 4 h as a beige solid (2.9 g, 80%, 3: 1 mixture of diastereoisomers (3R, 4S) and (3S, 4S)): tR = 0.46 min (diastereoisomer (3R, 4S)) and 0.48 min (diastereoisomer (3S, 4S)) (LC-MS 3); ESI-MS: 268 [M + H] + (LC-MS 3).
[00774] H NMR data for the compounds of the examples above are provided in the following table.











Additional physical properties
[00775] The crystalline materials obtained in examples 10 and 18, lots A - E were further characterized as follows. Determination of melting point
[00776] The melting point was determined by differential scanning calorimetry (DSC). DSC was measured using the DSC 2000 from TA Ins-instruments, Serial No. 100036. A 1 to 5 mg sample was weighed on a standardized aluminum tray (tray + lid, TA 900786.901, 900779.001). The instrument was operated using the Thermal Advantage Q-Series V.2.6.0.367 program and the Thermal Advantage V.4.6.9 program. Thermal events were characterized using Universal Analysis V4.3A Buid 4.3.0.6. The samples were measured against an empty tray. The sample was treated according to the protocol below.
[00777] Step 1: BALANCE at -40 ° C
[00778] Step 2: HEAT 10 ° C / min / 300 ° C
[00779] Modulation: No
[00780] The obtained graphics are shown in Figures 1, 3, 5, 7, 9 and 11. X-Ray Powder Diffraction (PXRD):
[00781] A sample amount of about 2 - 5 mg is placed on a glass objective slide and centered on the X-ray beam in a Bruker D8 GADDS Discover with a CuKa anode (Serial No. 002482). The sample-detector distance was 30 cm. Two frames were recorded between 5 and 40 ° 2-theta. The frames were merged using the GADDS 4.1.27 program. The assessment was conducted using EVA 10.0.0.
[00782] The obtained graphics are shown in Figures 2, 4, 6, 8, 10 and 12.
[00783] The representative 2-theta peaks [°] are provided in the following tables: Figure 2 (PXRD Example 10)
Figure 4 (PXRD Example 18A)
Figure 6 (PXRD Example 18B)

Figure 8 (PXRD Example 180
Figure 10 (PXRD Example 18D)
Figure 12 (PXRD Example 18E)
Biological activity
[00784] The effectiveness of the compounds of the present invention as inhibitors of PI3 kinase can be demonstrated as follows: Preparation of compound dilutions (384 wells)
[00785] The test compounds were dissolved in DMSO (10 mM) and transferred to 1.4 ml flat-bottomed or V-shaped Matrix tubes that carry a single 2D matrix chip from individual Novartis compound hubs. The numbers on these chips were distinctly linked to Novartis Pharma Numbers. Stock solutions were stored at -20 ° C if not used immediately. For the test procedure, the bottles were thawed and identified by a scanner through which a worksheet was generated, which guided the subsequent work steps.
[00786] The compounds were manually diluted in DMSO for individual experiments (96 wells that allow 10 cpds in 8 concentrations (single points) as described or prepared as described below if tested for profiling in 384 wells. This format made it possible to test no maximum 40 individual test compounds at 8 concentrations (single points) including 4 reference compounds.The dilution protocol included the production of "predilution plates", "master plates" and "assay plates".
[00787] Pre-dilution plates: 96-well polypropylene plates were used as pre-dilution plates. A total of 4 predilution plates were prepared including 10 test compounds each on positions A1 - A10 on the plate, a standardized compound on A11 and a control with DMSO on A12. The pattern of the dilution steps is summarized in Table 1. The programs were written to run these pipetting steps with HamiltonSTAR robots. Table 1. Dilution standard for predilution plates


[00788] DMSO was saturated with H2O to a final concentration of 10%. Vol: Volume, Cone .: Concentration, Dilution Prop .: Dilution Ratio, Fin.c: final concentration.
[00789] Master plates: 100 pL of individual compound dilutions including the standardized compound and the controls of the 4 "predetermination plates" were transferred to a 384 well "master plate" including the following 1,820 concentrations. 564, 182, 54.6, 18.2, 5.46, 1.82 3 0.546 pM, respectively in 90% DMSO.
[00790] Assay plates: Identical "assay plates" were prepared by pipetting 50 nl of each of the compound dilutions of the "master plates" into 384 well "assay plates". The compounds were mixed with 4.5 pL of test components plus 4.5 pL of enzyme which corresponds to a dilution of 1: 181, allowing the final concentration of 10, 3.0, 1.0, 0.3, 0 , 1, 0.03, 0.01 and 0.003 pM, respectively. The preparation of the "master plates" was handled by the Matrix PlateMate Plus robot and the replication of the "test plates" by the HummingBird robot. Method for generating expression constructs
[00791] PI3Ko, PI3Kβ, PI3KÕ and catalytically active human mTOR were cloned, expressed and purified as described (Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chène P, de Pover A, Schoemaker K, Fabbro D, Gabriel D, Simonen M, Murphy L, Finan P, Sellers W, Garcia-Echeverria C (2008), Mol Cancer Ther. 7: 1851-63 and Maira SM, Pecchi S, Brueggen J, Huh K , Schnell C, Fritsch C, Nagel T, Wiesmann M, Brachmann S, Dorsch M, Chène P, Schoemaker K, De Pover A, Menezes D, Fabbro D, Sellers W, Garcia-Echeverria C, Voliva CF (2011), Mol Cancer Ther. Accepted). Biochemical assays for PI3Kalfa and PI3Kbeta
[00792] The ATP detection reagent based on luminescence KinaseGIo was obtained from Promega (Cat. No. V6714, Lot No. 236161) through Catalys, Wallisellen, Switzerland. (L-alpha-phosphatidylinositol (Pl), Liver, Bovine) was obtained from Avanti Polar Lipid (Cat. No. 840042C, Lot # LPI-274), Phosphatidylinositol-4,5-bisphosphate (PIP (4,5) 2 (Avanti, Cat. No. 840046X) or La-phosphatidylinositol (Pl) was obtained from Avanti Polar Lipid (Cat. No. 840042C, Lot # LPI-274). La-phosphatidylserine (PS) was obtained from Avanti Polar Lipid (Cat. No. 840032C), n -Octilglicosideo Avanti Polar Lipid (Cat. No. 10634425001). Luminescence is a well-established reading to determine ATP concentrations and can then be used to track the activity of various kinases regardless of their substrates. The Gio Luminescent Kinase Kinase Assay (Promega, Macon / WI, USA) is a homogeneous HTS method of measuring kinase activity by quantifying the amount of ATP remaining in solution after the kinase reaction.
[00793] 50 nL of compound dilutions were dispensed into 384-well Non Binding Styrene (NBS) small volume black plates (Costar Cat. No. NBS # 3676) as described in section 8.2. L-α-phosphatidylinositol (PI), supplied as a 10 mg solution; mL in methanol, was transferred to a glass tube and dried under a flow of nitrogen. It was resuspended in 3% octylglycoside by centrifugation and stored at 4 ° C. 5 pL of a PI / OG mixture with the PI3Ka and PI3Kb subtypes was added. The kinase reactions were initiated by adding 5 μl of ATP mixture containing 10 μl of 10 mM Tris-HCI pH 7.5, 3 mM MgCh, 50 mM NaCI, 0.05% CHAPS, 1 mM DTT in a final volume and 1 pM ATP and occurred at room temperature. The reactions were stopped with 10 µl of KinaseGIo and the plates were read 10 min later in a Synergy2 reader, using an integration time of 0.1 seconds per well. 2.5 pM NVP-BGT226 (standard) was added to the assay plates to generate 100% inhibition of the kinase reaction and 0% inhibition was given by the solvent vehicle (90% DMSO in water). NVP-BGT226 was used as the reference compound and included on all assay plates in the form of 16 dilution points in duplicate.
[00794] The IC50 values of the percentage of inhibition of each compound in 8 concentrations (usually 10, 3.0, 1.0, 0.3, 0.1.0.03, 0.01 and 0.003 pM) n = 2 were derived by adjusting a sigmoidal dose-response curve for a plot of the assay reading on the inhibitory concentration as described. All adjustments were made using the XLfit4 program (ID Business Solutions, Guildford, UK). Biochemical assays for PI3Kdelta, PI3Kqama
[00795] The TR-FRET Adapta ™ Universal Kinase Kit was purchased from Invitrogen Corporation * Carlsbad / CA, USA) * No. Cat. PV5099). The kit contains the following reagents: Antibody Adapta Eu anti-ADP (anti-ADP antibody labeled with Europium in buffered saline, Cat. No. PV5097), ADP tracker marked Alexa Fluor® 647 (ADP tracker marked Alexa Fluor® 647 in HEPES buffered saline, Cat. No. PV5098), patented dilution buffer TR-FRET pH 7.5 (Cat. No. PV3574).
[00796] The substrate PIK3CD of Phosphatidylinositol was obtained from Invi-trogen (vesicles consisting of 2 mM PI in 50 mM HEPES pH 7.5; Cat. No. PV5371). The substrate PI3CG of Phosphatidylinositol-4,5-bisphosphate (PIP (4,5) 2 was obtained from Invitrogen (PIP2: PS large unilamellar vesicles consisting of 1mM PIP2: OS 19 mM in HEPES 50 mM pH 7.5, MgCh 3 mM, EGTA 1mM; Cat. No. PV5100).
[00797] Resonance Energy Transfer by Time-Resolved Fluorescence (TR-FRET) is a technology based on the transfer of energy between two adjacent dyes, from an electron excited in a dye (0 donor) to an electron of a dye ad- jacente (0 acceptor) through resonance, then released as a photon. This energy transfer is detected by an increase in the fluorescence emission from the acceptor and a decrease in the fluorescence emission from the donor. TR-FRET assays for protein kinases use chelates of a long-lived Lanthanide Térbio or Europius as the donor species that overcomes the interference of the autofluorescent compound or the light dispersion of precipitated compounds, by introducing a delay after of excitation by an excitation source of flash light. The results are generally expressed as a proportion of the intensities of the acceptor and donor fluorophores. The raciometric nature of such a value corrects differences in test volumes between wells, as well as corrects the effects of shutdown due to colored compounds. The Adapta ™ assay can be divided into two phases: a kinase reaction phase and an ADP detection phase. In the kinase reaction phase, all components of the kinase reaction are added to the well and the reaction is allowed to incubate for a specific time adjustment period for each kinase. After the reaction, a solution of anti-ADP antibody labeled with Europio, ADP tracker marked with Alexa Fluor® 647 and EDTA (to stop the kinase reaction) are added to the test well. The ADP formed by the kinase reaction will displace the Alexa Fluor® 647-labeled ADP tracker from the antibody, resulting in a decrease in the TR-FRET signal. In the presence of an inhibitor, the amount of ADP formed by the kinase reaction is reduced and the resulting intact antibody-marker interaction maintains a high TR-FRET signal. In the Adapta ™ assay, the Europium-labeled anti-ADP donor antibody is excited at 340 nm and will transfer its energy to the acceptor (ADP tracker labeled with Alexa Fluor® 647). The emission from Alexa Fluor® 647 can be monitored with a filter centered at 665 nm because it is located between the emission peaks of the donor which is measured at 615/620 nm.
[00798] 50 nl_ of compound dilutions were dispensed on 384-well small-volume white polystyrene plates as described in section 2.2. Then, 5 pL of PI3Kd and PI3Kg and lipid substrate (Pl or PIP2: PS), followed by 5 pL of ATP (10 pL final assay volume) are incubated in RT. The standardized reaction buffer for the Adapta ™ TR-FRET assay contained 10 mM Tris-HCI pH 7.5, 3 mM MgCh, 50 mM NaCI, 1 mM DTT, 0.05% CHAPS. The reactions were stopped with 5 µl of an EDTA mixture containing the Eu-labeled anti-ADP antibody and the Alexa Fluor® 647-labeled ADP tracker in TR-FRET dilution buffer (patented by IVG). The plates were read 15 to 60 min later on a Synergy2 reader, using an integration time of 0.4 seconds and a delay of 0.05 seconds. The control for 100% inhibition of the kinase reaction was performed by replacing PI3K with the standardized reaction buffer. The control for 0% inhibition was given by the solvent solvent of the compounds (DMSO 90% in H2O). The standard compound NVP-BGT226 was used as a reference compound and included in all assay plates in the form of 16 dilution points in duplicate.
[00799] The data are analyzed using the Excel fit program or GraphPad Prism. The EC50 values were derived by adjusting a sigmoidal dose-response curve for a reading graph of the assay on the inhibitory concentration. All adjustments were made using the XLfit4 program (ID Business Solutions, Guildford, UK). The determination of the EC50 values of the percentage of inhibition of each compound in 8 concentrations (usually 10, 3.0, 1.0, 0.3, 0.1, 0.03, 0.01 and 0.003 pM) n = 2 were derived by adjusting a sigmoid dose-response curve for a reading graph of the assay on the inhibitory concentration. All adjustments were made with the XLfit4 program (ID Business Solutions, Guildford, UK). Biochemical assay for mTOR
[00800] TR-FRET assays for protein kinases use long-lived lanthanide chelates Terbium or Europium as the donor species that overcomes the interference of the autofluorescent compound or the light dispersion of precipitated compounds, by introducing a delay after excitation by an excitation source of flash light. The results are generally expressed as a proportion of the intensities of the acceptor and donor fluorophores. The raciometric nature of such a value corrects differences in test volumes between wells, as well as corrects the effects of shutdown due to colored compounds.
[00801] Binding assays are based on the binding and displacement of ATP-labeled kinase inhibitors competitive with Alexa Fluor® 647 to the kinase of interest. Invitrogen's "Tracers Kinase" have been developed to target a wide range of kinase targets and are based on kinase inhibitors competitive with ATP, making them suitable for the detection of any compounds that bind to the ATP site or a allosteric site, changing the conformation of the ATP site. Inhibitors that bind to the ATP site include both Type I kinase inhibitors, which bind only to the ATP site, and Type II inhibitors (for example, Gleevec® / lmatinib, Sorafenib, BIRB-796), which bind to both the ATP site and a hydrophobic site exposed in the DFG-out conformation (not active). Type III inhibitors are compounds that do not compete with ATP and are generally referred to as allosteric inhibitors. A study of 15 different Type III inhibitors showed that all but one compound were detected in the binding assay with power equivalent to the activity assays. The only exception was a competitive compound for the substrate and is therefore not a true allosteric inhibitor.
[00802] In contrast to most fluorescence-based kinase activity assays, LanthaScreen® Eu3 + Kinase Binding Assays can be read continuously, which facilitates the evaluation of compounds with slow binding kinetics. Also unlike most activity assays, binding assays can be performed using active or non-activated kinase preparations, which makes it possible to characterize compounds that preferentially bind to non-activated kinases, such as Gleevec® / lmatinib and some inhibitors allosteric.
[00803] In the Lanthascreen ™ kinase binding assay, the donor (anti-GST-Eu3 + antibody) is excited at 340 nm and will transfer its energy to the acceptor (competitive ATP kinase inhibitor marked with AlexaFluor® 647 = Tracer 314) . The emission of Tracer-314 (AlexaFluor® 647 inhibitor) can be monitored with a filter centered at 665 nm because it is located between the emission peaks of the donor, which is measured at 615/620 nm. The connection of both Tracer-314 and the anti-GST-Eu3 + antibody with the kinase results in a high degree of FRET from the Eu3 + donor fluorophore to the AlexaFluor® 647 acceptor fluorophore over Tracer-314. The binding of an inhibitor to the kinase competes for binding to the tracker, resulting in loss of FRET.
[00804] 50 nl_ of compound dilutions were dispensed on 384-well small volume white polystyrene plates as described in section 2.2. Then, 5 µl of GST-mTOR and anti-GST-Europio antibody followed by 5 µl of Tracer-314 (final 10 µl assay volume) are incubated in RT. The standardized reaction buffer for the assay for the Lanthascreen ™ kinase binding assay contained 50 mM HEPES pH 7.5, 50 mM MgCh, 1 mM EGTA, 0.01% Pluronic F-127. The plates are read 60 minutes later on a Synergy2 reader using an integration time of 0.2 microseconds and a delay of 0.1 microseconds.
[00805] To calculate the emission rate, the signal emitted at 665 nm from the acceptor (Tracer-314 marked with AlexaFluor® 647) is divided by the signal emitted at 620 nm from the donor (anti-GST Eu3 + antibody).
[00806] The control for 0% inhibition was given by the solvent carrier of the compounds (DMSO 90% in H2O). The control for 100% relative inhibition was performed by adding 10 pM to the mixture containing GST-mTOR and anti-GST Europio antibody. An additional control for 0% absolute inhibition is given by the anti-GST Eu3 + antibody without GST-mTOR. Cellular assays for PI3Kalfa, beta and delta
[00807] AlphaScreen (Amplified Luminescent Proximity Homogeneous Assay, ALPHA, Perkin Elmer) is a non-radioactive sphere-based proximity assay technology for studying biomolecular interactions in a homogeneous microtiter plate format. The trade name SureFire denotes AlphaScreen assays that are adapted to quantify the phosphorylation of endogenous cellular proteins in cell lysates, by using combined antibody pairs, which consist of an anti-phospho-kinase antibody and an anti-kinase. The assay allows the characterization of kinase signaling in cells as well as the measurement of kinase inhibitory effects. AlphaScreen technology provides several advantages over standardized testing techniques such as ELISA, as it avoids lengthy washing procedures and reduces plate handling. In addition, it is miniaturizable to at least a 384-well format and provides sensitivity below the femtomolar range, dependent on the affinity of the antibodies included in the individual AlphaScreen SureFire assay kit. High sensitivity is achieved by an intrinsic amplification mechanism, which involves the production of isolated oxygen molecules. SureFire assay kits are commercially available for specific targets and include validated antibody pairs (PerkinEImer). This report describes common procedures applied for AlphaScreen SureFire assays and the corresponding semi-automated steps for routine kinase inhibitor profiling in cell-based assays.
[00808] Rat-1 cell lines that stably overexpress isoforms of PI3K class I Rat-1 pBABEpuro Myr-HA-hp110 delta (Rat-1_PI3Kdelta) and Rat-1 pBABEpuro Myr-HA-hp1 Walfa (Rat- 1_PI3Kalfa) and Rat-1 pBABEpuro Myr-HA-hp110 beta (Rat-1 _PI3beta) were prepared as described (Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chène P, by Pover A, Schoemaker K, Fabbro D, Gabriel D, Simonen M, Murphy L, Finan P, Sellers W, García-Echeverría C (2008), Mol Cancer Ther. 7: 1851-63 and Maira SM, Pecchi S, Brueggen J, Huh K , Schnell C, Fritsch C, Nagel T, Wiesmann M, Brachmann S, Dorsch M, Chène P, Schoemaker K, De Pover A, Menezes D, Fabbro D, Sellers W, García-Echeverría C, Voliva CF (2011) , Mol. Cancer Ther., Accepted). All cell lines were cultured in complete growth medium (DMEM rich in glucose, 10% (v / v), fetal bovine serum 1% (v / v) MEM NEAA, HEPES 10mM, L-glutamine 2mM, puromycin (10 pg / mL for Rat-1_PI3Kdelta and Rat-1_PI3Kalfa, 4 ug / mL for Rat-1_PI3beta), 1% (v / v) Pen / Strep) up to 90% confluence at 37 ° C / 5% CO2 / 90% humidity in a CO2 humidified incubator and were divided twice a week.
[00809] The following materials were used for the detection of p-AKT (S473) in Rat-1 cell lysates: Dulbecco-modified Eagle medium (DMEM) rich in glucose (Gibco Invitrogen, Basel, Switzerland, No. Cat. 41965), Qualified (Hl FBS; Gibco Invitrogen, Basel, Switzerland, Lot No. 16140), Non-essential amino acids (NEAA; Gibco Invitrogen, Basel, Switzerland, Cat. No. 11140), HEPES (Gibco Invitrogen, Basel, Switzerland, Cat. No. 15630), Penicillin / Streptomycin (Pen / Strepto, 100x; Gibco Invi-trogen, Basel, Switzerland, Cat. No. 15140-122), L -Glutamine (Gibco Invitrogen, Basel, Switzerland, Cat. No. 25030), Puromycin (Sigma Al-drich, Buchs, Switzerland, Cat. No. P9620), DMSO (MERCK, Dietikon, Switzerland, Cat. 8.02912.2500), H2O, MilliQ-H2O unless otherwise determined (MILLIPORE QGARDOOR1, Millipore, Zug, Switzerland), Bovine serum albumin (BSA; Sigma Aldrich, Buchs, Switzerland Cat. A8412), SureFire p-Akt 1/2 (Ser473) Assa y Kit (PerkinenElmer, Schwerzenbach, Switzerland, Cat. No. TGRAS50K).
[00810] The SureFire assay of p-Akt (S473) measures endogenous cell Akt 1/2 phosphorylation in Ser473 in cell lysates. Using Rat-1 cells that stably express labeled myr-HA versions of PI3Kdelta, PI3Kalfa or PI3Kbeta p110 catalytic subunit isoforms, the assay was developed as a two-plate protocol in a 384-well format.
[00811] To test the compound, the cells were seeded at a density of 4000 (Rat-1_PI3Kalpha), 7500 (Rat-1_PI3Kalpha), or 6200 (Rat-1_PI3Kbeta) cells in 20 ul of complete growth medium in plates of cell cultures treated with 384 wells and grown at 37 ° C / 5% CO2 / 90% humidity for 24 h. Just before the transfer of the compound, the complete medium was removed, 30 µl of assay buffer (glucose-rich DMEM, 1x MEM NEAA, 10 mM HEPES, 2 mM L-glutamine, 0.1% BSA (w / v)) 10 µl of compound predilutions were added to the cells. To test after February 2010, the assay buffer was replaced with complete growth medium, which revealed similar results (data not shown). After treatment with the compound for 1 h, the cells were lysed by adding 20 µl of lysis buffer supplemented with 0.24% (w / v) BSA. Detection of p-AKT (Ser473) was performed with the SureFire Assay Kit for p-Akt 1/2 (Ser473) according to the manufacturer's instructions using 5 μl of the cell lysate in a total detection volume of 12 μl.
[00812] The IC50 values of the percentage of inhibition of each compound in 8 concentrations (usually 10, 3.0, 1.0, 0.3, 0.1.0.03, 0.01 and 0.003 pM) n = 2 were derived by adjusting a sigmoidal dose-response curve for a plot of the assay reading on the inhibitory concentration. All adjustments were made using the XLfit4 program (ID Business Solutions, Guildford, UK). Cell assay for mTor
[00813] A cell-based assay (384-well format) was developed to determine the effects of the compound on cell mTOR kinase activity in MEF cells (mouse embryo fibroblasts) derived from mice lacking TSC1 (Complex Tuberosclerosis 1), a potent suppressor of mTOR kinase activity. Due to the absence of TCS1, the mTOR kinase is constitutively activated resulting in permanent phosphorylation of Thr 389 of S6 kinase (S6K1), which is one of the downstream targets of mTOR.
[00814] Using a SureFire kit that allows determining the phosphorylation of Thr389 from S6K1, an assay was developed, validated and implemented in the AlphaScreen format that allows the quantitative determination of phospho-T389 from S6K1 in cell lysates. The treatment of MEF TSC1 - / - cells with specific inhibitors of mTOR (or the mTOR pathway), reduced the levels of phospho-T389 of S6K1 depending on the dose, allowing the calculation of IC50 values. These were in agreement with those obtained with the biochemical assay of binding to the mTOR ATP, allowing a quantitative comparison of the potency of mTOR inhibitors.
[00815] MEFs TSC1 - / - cells (Kwiatkowski, DJ, Zhang, H., Bandura, JL, Heiberger, KM, Glogauer, M., el-Hashemite, N., and Onda, H. (2002) Hum. Mol. Genet. 11, 525-534) were grown in DMEM medium rich in glucose supplemented with 10% FBS (Invitrogen), 2mM Glutamine and 1% (w / v) Penicillin / Streptomycin at 37 ° C, 5% CO2.
[00816] The SureFire kit for the determination of P70S6 kinase phosphorylation was purchased from PerkinElmer (p70S6K p-T389, # TGR70S50K) and the test was carried out according to the supplier's instructions and according to the generic method for the Sure- Fire. Briefly, 5 pL of cell lysate per well were transferred to white proxy plates with 384 wells (for luminescence reading) and mixed with 7 pL of A and 5 pL of B (final volume: 12 pL). After 3 h of incubation in the dark at RT, the luminescence was read with the Envision Reader (PerkinElmer). Untreated cells were used as a control (upper control) and cells treated with 3 pM BEZ235 were used as a lower control. The test window between the signals obtained for the upper and lower controls was defined as 100% and the effects of the compound were expressed as a percentage of inhibition. IC50 values were calculated from dose response curves by graphic extrapolation.
[00817] The results obtained using the tests described above are provided in the tables below where SEM is 0 standard error of the mean and n is the number of measurements of the data. Biochemistry of PI3Kalfa


a different, separate measure gave a value of <0.003 µM. Biochemistry of PI3Kbeta

Biochemistry of PI3Kd elta

Biochemistry of PI3Kgama


* 2 of the 3 values> 9.1. No SEM calculation was possible. ** Both values> 9.1. No SEM calculation was possible. Cellular PI3Kalfa assay

Cellular PI3Kbeta assay


1 fourth measurement 3.9 uM, atypical 2 * The second value was> 10, therefore, no SEM calculation was possible. Cellular PI3Kdelta assay


* The second value was> 10, Therefore, no calculation of SE s mTOR cell assay

1 The second value was> 2.27, so no SEM calculation was possible. 2 * 3 of the 4 values were> 2.27, therefore, no SEM calculation was possible. 3 ** 3 of the 5 values were> 2.27, therefore, no SEM calculation was possible. 4 *** All values were> 2.27, so no SEM calculation was possible.
[00818] The off-target effect (evidence of tubulin binding) was measured as follows. Description of the Cytospin assay
[00819] Cytospin cell cycle arrest assay in G2 / M to detect tubulin binding activities (off target) of MAPP derivatives: 5 x 105 A2058 cells were plated in a 6-well cluster with 2 mL of DMEM (rich in glucose containing 1% sodium pyruvate, 1% glutamine and 10% FCS). 18 hours later, the test items were added at a concentration of 5 pM (seeding 1 pL of a 10 mM solution of the test item). 24 hours later, the cells were trypsinized and transferred to 15 ml conical tubes. The cells were then pelleted by centrifugation and resuspended with PBS / O (containing 10% FCS). The cells are counted with a CASY counter and each sample is equilibrated to 1 x 106 cells / ml. 200 pL (2 x 105 cells) were then transferred to 1.5 ml Cytospin tubes (Heraeus Sepatec, Ref 1152) and centrifuged for 5 min at 50 g at 4 ° C with a Cytospin system, containing a Sepatech system (Heraeus, Ref . # 3425), fitted on top of a microscope slide (Thermo-Scientific, Ref. # PH040820. The cells were then fixed for 15 min at room temperature and stained with the Diff Quick® assay (Medion Diagnostics, Ref: # 130832 ), according to the manufacturer's recommendations. The condensed DNA that reflects the stop in G2 / M is revealed by the dotted staining in the cells, when examining the slides under a microscope. The staining was visually evaluated for the presence of condensed DNA. and a score where 0 = no condensed DNA observed (indicating no off-target activity), 1 = (indicating low off-target activity), 2 = (indicating average off-target activity), 3 = large amount of DNA observed condensate (indicating marked off-target activity).
[00820] The data obtained using this method is shown in the following table:

na = not accomplished

权利要求:
Claims (21)
[0001]
1. Compound, characterized by the fact that it presents Formula (I),
[0002]
2. A compound according to claim 1, characterized by the fact that: R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or - CH2OC (O) H; R3 = H; R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or R4 = H, and R5 = -CH3OU -CH2OH, or R4 = H or -CH3 and R5 = H or -CH3; or R3 = He R4 = H; R2 and R5 = - (CH2) 4-; or R4 = H and R5 = H; and R2 = -CH2OH, and R3 = -CH3; OR R2 = H or -CH3, and R3 = -CH2OH, or a pharmaceutically acceptable salt thereof.
[0003]
Compound according to claim 1 or 2, characterized in that: R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or - CH2OC (O) H; R3 = H; R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or R4 = H, and R5 = -CH3OU -CH2OH, or R4 = H or -CH3 and R5 = H or -CH3; or R4 = H and R5 = H; and R2 = -CH2OH, and R3 = -CH3; OR R2 = H or -CH3, and R3 = -CH2OH, or a pharmaceutically acceptable salt thereof.
[0004]
Compound according to any one of claims 1 to 3, characterized in that: R2 = -CH3, -CH2OH, -CH2OCH3, -CH2CH2OH or - CH2OC (O) H; R3 = H; R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or R4 = H, and R5 = -CH3OU -CH2OH, or R4 = H or -CH3 and R5 = H or -CH3, or a pharmaceutically acceptable salt thereof .
[0005]
Compound according to any one of claims 1 to 4, characterized by the fact that it presents Formula (IA '):
[0006]
6. Compound, according to claim 1, characterized by the fact that it presents Formula (IA):
[0007]
7. A compound according to claim 6, characterized by the fact that: R2 = -CH3OU -CH2OH; R3 = H; R4 = -CH3, -CH2OH or -CH2CH2OH, and R5 = H, or R4 = H, and R5 = -CH3OU -CH2OH, or R4 = H or -CH3 and R5 = H or -CH3, or a pharmaceutically acceptable salt thereof .
[0008]
8. Compound according to claim 7, characterized by the fact that: R2 = -CH3OU -CH2OH; R3 = H; R4 = -CH3, -CH2OH or -CH2CH2OH and R5 = H or R4 = He R5 = CH3OU -CH2OH, or a pharmaceutically acceptable salt thereof.
[0009]
A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, characterized in that it is selected from: (S) -3- (2'-Amino-2-morpholin-4- il-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-methyl-oxazolidin-2-one, (S) -3- (2'-Amino-2-morfolin-4-yl- 4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-hydroxymethyl-5,5-dimethyl-oxazolidin-2-one, 3- (2'-amino-2-morpholino-4' - ( racemic trifluormethyl) -4,5'-bipyrimidin-6-yl) - 4- (hydroxymethyl) -4-methyloxazolidin-2-one, (S) -3- (2'-amino-2-morpholino-4 '- ( trifluormethyl) -4,5'-bipyrimidin-6-yl) -4- (hydroxymethyl) -4-methyloxazolidin-2-one (absolute stereochemistry not determined), (R) -3- (2'-amino-2-morpholino -4 '- (trifluormethyl) -4,5'-bipyrimidin-6-yl) -4- (hydroxymethyl) -4-methyloxazolidin-2-one (absolute stereochemistry not determined), (3aS, 7aS) -3- (2 '-Amino-2-morfolin-4-yl-4'-trifluormethyl- [4,5'] bipyrimidinyl-6-yl) -hexa-hydro-benzoxazol-2-one, (S) -3- (2'- Amino-2-morfolin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6 -yl) -4-methoxymethyl-oxazolidin-2-one, (4S, 5S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6 -yl) -4-hydroxymethyl-5-methyl-oxazolidin-2-one, (S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl -6-yl) -4-hydroxymethyl-oxazolidin-2-one, (4S, 5R) -3- (2'-Amino-2- (D8-morpholin-4-yl) -4'-trifluormethyl- [4, 5 '] bipyrimidinyl-6-yl) -4-hydroxymethyl-5-methyl-oxazolidin-2-one, (S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [ 4,5 '] bipyrimidinyl-6-yl) -4- (2-hydroxy-ethyl) -oxazolidin-2-one, (4S, 5R) -3- [2'-Amino-2 - ((S) -3 -methyl-morpholin-4-yl) -4'- trifluormethyl- [4,5 '] bipyrimidinyl-6-yl] -4-hydroxymethyl-5-methyl-oxazolidin-2-one, ester (4S, 5R) -3 - Formic acid (2'-amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -5-methyl-2-oxo-oxazolidin-4-ylmethyl (S) -3- [2'-Amino-2 - ((S) -3-methyl-morpholin-4-yl) -4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl] - 4-methyl-oxazolidin-2-one, (S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -5- hydroxymethyl-oxazoli din-2-one, (4S, 5R) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -5-hydroxymethyl- 4-methyl-oxazolidin-2-one, (S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -5- methyl-oxazolidin-2-one, (S) -3- (2'-amino-2-D8-morpholino-4 '- (trifluormethyl) - [4,5'-bipyrimidin] -6-yl) -4-methyloxazolidin -2-one, (4S, 5R) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-hydroxymethyl-5 -methyl-oxazolidin-2-one, (4S, 5S) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -5 -hydroxymethyl-4-methyl-oxazolidin-2-one, (R) -3- (2'-Amino-2-morpholin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -5-hydroxymethyl-oxazolidin-2-one, (3aR, 6aR) -3- (2'-amino-2-morpholino-4 '- (trifluoromethyl) - [4,5'-bipyrimidin] -6-yl) tetra -hydrofuro [3,4-d] oxazol-2 (3H) -one, (3aR *, 6R *, 6aR *) - 3- (2'-Amino-2-morpholino-4 '- (trifluoromethyl) - [4 , 5'-bipyrimidin] -6-yl) -6-hydroxyhexa-hydro-2H-cyclopenta [d] oxazol-2-one racemic, (3aR, 6R, 6aR) - (2'-Amino-2-morpholino-4 '- (trifluormethyl ) - [4,5'- bipyrimidin] -6-yl) -6-hydroxyhexa-hydro-2H-cyclopenta [d] oxazol-2-one, (3aS, 6S, 6aS) - (2'-Amino-2- morpholino-4 '- (trifluormethyl) - [4,5'-bipyrimidin] -6-yl) -6-hydroxyhexa-hydro-2H-cyclopenta [d] oxazol-2-one, and (4S, 5R) -3- (2'-Amino-2-morpholino-4 '- (trifluormethyl) - [4,5'-bipyrimidin] -6-yl) -5- (2-hydroxyethyl) -4-methyloxazolidin-2-one.
[0010]
10. Compound, or a pharmaceutically acceptable salt thereof according to claim 9, characterized by the fact that it is selected from: (4S, 5R) -3- [2'-Amino-2 - ((S) -3- methyl-morpholin-4-yl) -4'- trifluormethyl- [4,5 '] bipyrimidinyl-6-yl] -4-hydroxymethyl-5-methyl-oxazolidin-2-one, (4S, 5R) -3- ( 2'-Amino-2-morfolin-4-yl-4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl) -4-hydroxymethyl-5-methyl-oxazolidin-2-one or (4S, 5R) -3- (2'-Amino-2-morpholino-4 '- (trifluoromethyl) - [4,5'-bipyrimidin] -6-yl) -5- (2-hydroxyethyl) -4-methyloxazolidin-2-one.
[0011]
11. Compound according to claim 1, characterized by the fact that it is (4S, 5R) -3- (2'-amino-2-morpholin-4 '- (trifluormethyl) - [4,5'] bipyrimidin-6-yl) -4-hydroxymethyl-5-methyl-oxazolidin-2-one, with the structure:
[0012]
12. A compound according to claim 1, characterized by the fact that it is (4S, 5R) -3- [2'-amino-2 - ((S) -3-methyl-morpholin-4-yl) -4'-trifluormethyl- [4,5 '] bipyrimidinyl-6-yl] -4-hydroxymethyl-5-methyl-oxazolidin-2-one, having the structure:
[0013]
13. A compound according to claim 1, characterized by the fact that it is (4S, 5R) -3- (2'-amino-2-morpholino-4'- (trifluormethyl) - [4,5'- bipyrimidin] -6-yl) -5- (2-hydroxyethyl) -4-metioxazolidin-2-one, having the structure:
[0014]
Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound, as defined in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
[0015]
15. Pharmaceutical composition according to claim 14, characterized in that it is formulated as a solid dispersion of said compound.
[0016]
16. Combination, characterized in that it comprises a therapeutically effective amount of a compound, as defined in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutically active agents.
[0017]
A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, characterized in that it is for use as a medicament.
[0018]
18. Use of a compound, as defined in any of claims 1 to 13, or of a pharmaceutically acceptable salt thereof, characterized by the fact that it is in the manufacture of a medicament for the treatment of cancer.
[0019]
19. Use, according to claim 18, characterized by the fact that the cancer is selected from a solid tumor, a brain carcinoma, a kidney carcinoma, a liver carcinoma, an adrenal gland carcinoma, a bladder carcinoma , breast carcinoma, stomach carcinoma, esophageal carcinoma, ovarian carcinoma, colon carcinoma, rectal carcinoma, prostate carcinoma, pancreatic carcinoma, lung carcinoma, carcinoma of the lung of the vagina, a thyroid carcinoma, sarcoma, glioblastomas, multiple myeloma or gastrointestinal cancer, a neck tumor, a head tumor, squamous cell carcinoma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, plasma cell myeloma, Hodgkin's lymphoma or leukemia.
[0020]
20. A compound according to any one of claims 1 to 13, characterized by the fact that it is in amorphous form.
[0021]
21. Pharmaceutical composition according to claim 14 or 15, characterized by the fact that said compound is in amorphous form.

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law|

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2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2019-12-17| B07E| Notice of approval relating to section 229 industrial property law|

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2019-12-24| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|

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2020-06-30| B09A| Decision: intention to grant|

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2020-09-01| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 22/02/2013, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201261602954P| true| 2012-02-24|2012-02-24|

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US61/602,954|2012-02-24|

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US201261736707P| true| 2012-12-13|2012-12-13|

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US61/736,707|2012-12-13|

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PCT/IB2013/051443|WO2013124826A1|2012-02-24|2013-02-22|Oxazolidin- 2 -one compounds and uses thereof as pi3ks inhibitors|

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